IE52595B1 - New steroid derivatives substituted at position 11beta,process and intermediates for preparing them,their use as medicaments and the compositions containing them - Google Patents

Abstract

Novel 19-nor steroids and 19-nor-D-homo-steroids of the formula <IMAGE> I' wherein R1 is an organic radical of 1 to 18 carbon atoms containing at least one atom selected from the group consisting of nitrogen, phosphorous and silicon with the atom immediately adjacent to the 11-carbon atom being carbon, R2 is a hydrocarbon of 1 to 8 carbon atoms, X is selected from the group consisting of a pentagonal ring and a hexagonal ring optionally substituted and optionally containing a double bond, B and C together form a double bond or an epoxy group, the C=A group at position 3 is selected from the group consisting of C=O, ketal, <IMAGE> -C=NOH, -C=NOAlK3 and =CH2, AlK1, AlK2 and AlK3 are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having anti-glucocorticoid activity and a process for their preparation. [US4386085A]

Description

New steroid derivatives substituted at position 11β, process and intermediates for preparing them, their use as medicaments and the compositions containing them.

The present invention relates to new 19-nor steroid or 19-nor D-homosteroid compounds substituted at position lip, a process for preparing them, their use as medicaments, the compositions containing them and the new intermediates obtained.

The subject of the invention is the compounds of formula (I'): 52585 C A at position 5 represents an oxo group free or blocked in the form of a ketal, a I ϊ in which R^ represents an organic radical containing ·; from 1 to 18 carbon atoms, containing at least one nitrogen, phosphorus or silicon atom, the atom immediately ajacent the carbon at position 11 being I a carbon atom, R2 represents a hydrocarbon radical i containing from.l to 8 carbon atoms, 27 represents the | residue of a pentagonal or hexagonal ring, possibly i i substituted and possibly bearing an unsaturation,, | the gro 10 which i group C a group C=NOH, a group C=NO-alk^ or a group CH,,, alk-p ( alk2, and alk^ representing an alkyl radical containing I from 1 to 8 carbon atoms or an aralkyl group containing j from 7 to 15 carbon atoms and B and C together form a double bond or an epoxide bridge, as well as their salts of addition with acids.

Freferably R2 represents a straight or branched saturated alkyl radical, containing from 1 to 4 carbon atoms, for example a methyl, ethyl, n-propyl or butyl radical. j WheaAlkjj alk2 or alk^ represents an alkyl radical, j this is preferably the methyl, ethyl, n-propyl or isopropyl ( i radical. j ( i When alkj, alk9 or alk^ represents an aralkyl radical, this is preferably the benzyl radical.

Preferably X represents the residue of a possiblysubstituted pentaganal ring.

The invention extends, of course, to the addition salts with acids of the compounds of formula (I1) such as, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, and aspartic acids, alkane sulphonic acids such as methane or ethane sulphonic acids, arylsulphonic acids such as benzene or paratoluene sulphonic acids and arylcartcxylic acids.

The subject of the invention is especially the compounds of formula (I1), as defined before, corresponding to the formula (I) : 52595 , in which Rp R^, X and A are defined as before.

The subject of the invention is, more particularly,the compounds of formula (I*), for which R^ represents a methyl radical.

The subject of the invention is especially the compounds of formula (I') for which X represents the residue of a ring of formula; in which R2 ^eeps the same meaning as before, the dotted line-at 16 - 17 symbolizes the possible presence of a double bond, Y represents the radical I' C I R, in which n represents the number 1 or 2, R^ represents a hydrogen atom, an alkyl radical containing from 1 to 8 carbon atoms, an .alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, an aryl radical containing from 6 to 145 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, Rg, being the same as or different from R^, can take one of the values indicated for R^ and can also represent a hydroxyl radical, R^ and R^, being the same or different, represent either a hydrogen atom, or a radical OH, Oalk^ or O-CO-alk^, alk^ and alk^ representing an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, or a radical 0 or a radical II -c-ch2oh -COCHgOCOalkg, in which alkg represents an alkyl radical containing from 1 to 8 carbon atoms, possibly substituted, or an aralkyl radical containing from 7 to 15 carbon atoms or a radical CO-CO^H or CO-COgalk? in which alk? represents an alkyl radical containing from 1 to 8 carbon atoms, or NHalko I 8 a radical -0=0, or a radical -0=0 , in which alkg represents an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or a radical -CsN, or R^ and R^ together form a radical HC-0 Z^ in which represents a hydrogen atom, 52585 an alkyl radical or an acyl radical containing from 1 to 8 carbon atoms and Zg represents an alkyl radical containing from 1 to 8 carbon atoms.

R^ is preferably different from Rg.

When R^ or Rg represents an alkyl radical, this is preferably the methyl or ethyl radical.

When R^ or Rg represents an alkenyl radical, this is preferably the vinyl, isopropenyl or allyl radical.

When R^ or Rg represents an alkynyl radical, this is 10 preferably the ethynyl or propynyl radical.

When Rtj or Rg represents an aryl or aralkyl radical, this is preferably the phenyl or benzyl radical.

When Rj or R4 represents a radical Oalk^ or OCOalk^, alk^ and alk^ represent preferably a methyl, ethyl, n-propyl, butyl, pentyl, hexyl or benzyl radical.

When R^ or R^ represent an alkenyl radical, this is preferably the vinyl, isopropenyl, allyl or 2-methylallyl radical.

When Rj or R^ represents an alkynyl radical, this is 20 preferably the radical -CsCH or -CsC-alkg, alkg representing preferably a methyl, ethyl, propyl, isopropyl, isopropenyl, butyl, benzyl or trifluoromethyl radical.

Alkg, alk? and alkg represent preferably one of the preferred values of alk^ or alkg.

The preferred compounds are those for which the radicals R^ and R^ are different except in the case in which R^ and R^ each represent a hydrogen atom.

Among the preferred values of the radical ^/°H -σ, i -σ, '% l'„ 'GsC-CHj 'CSCH -c; -nh(ch2)2ch5 ΌΗ 52S9S ' in which Z^ represents a hydrogen atom, an alkyl radical containing from 1 to 8 carbon atoms or an acyl radical containing from 2 to 8 carbon atoms, for example an acetyloxy or benzoyl radical and Zg represents an alkyl radical containing from 1 to 8 carbon atoms, for example a methyl radical.

The subject of the invention is especially the compounds of formula (I1) for which the ring D does not bear any ethylenic unsaturation, R^ and Rg represent a hydrogen atom and n is equal to 1, as well as the compounds for which C=A represent an oxo group.

The subject of the invention is, more particularly, the compounds of formula (I1) for which R^ represents a hydrocarbon radical containing from 1 to 18 carbon atoms and containing at least one nitrogen atom.

Among these compounds, there may be mentioned especially the compounds for which R^ represents a primary, secondary or tertiary alkyl radical containing from 1 to 8 carbon atoms, Containing one or more heteroatoms selected from the group constituted by oxygen, nitrogen and sulphur, of which at least one is a nitrogen atom, or substituted by a heteroeycle containing at least one nitrogen atom.

By alkyl radical there is understood preferably the methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tertbutyt, pentyl, hexyl, cyclopropyl, cyclobutyl, cyelopentyl or cyclohexyl radical. 595 By heterocjcle containing at least one nitrogen atom, there may he mentioned the 2-, 3- or h-pyridyl radical, or the thiazolyl or piperidinyl radicalThere may also be mentioned as preferred compounds of the invention the compounds for which R^ represents a heterocyclic radical containing at least one nitrogen atom, possibly substituted by an alkyl radical containing from 1 to 8 carbon atoms.

By heterocyclic radical there is understood preferably one of the radicals mentioned above.

When R^ represents a heterocyclic radical containing at least one nitrogen atom, substituted by an alkyl radical, this is most often a heterocyole substituted by a methyl, ethyl or n-propyl radical.

Among the preferred compounds of the invention there may be mentioned also the compounds for which R^ represents an aryl or aralkyl radical bearing an amine function , in which R? and Rg represent an alkyl radical containing from 1 to 8 carbon atoms or a primary secondary or tertiary alkyl radical containing from 1 to 8 carbon atoms, containing one or more heteroatoms selected from the group constituted by oxygen, nitrogen and sulphur, of which at least one is a nitrogen atom, or substituted by a heterocycle containing at least one nitrogen atom. 52595 > By alkyl radical there is understood preferably one of the radicals mentioned above.

By aryl or aralkyl radical there is understood preferably the phenyl or benzyl radical.

By heterocyclic radical there is understood preferably one of the heterocyclic radicals mentioned above.

The subject of the invention is especially the compounds for which R^ represents a 2-jJ-or 4-pyridyl radical, a radical -(CH2)n " a radical a radical a radical CH.

CB5 (n>5) ,CH. '3 CH. '3 or a radical N-CH The subject of the invention is also, in particular, the compounds for which R^ represents a radical: Si(CH3)3 Among the compounds of the invention there may also be mentioned the compounds in which R^ contains an oxidised nitrogen atom, as well as those in which B and C together form an epoxy bridge.

Among the preferred compounds of the invention there may of course be mentioned the compounds of which the preparation is given further on in the experimental part and especially the compounds of Examples 1, 3, 4-, 8, 10, 11, 12, Id, 16, 17, 20, 22, 28 and 29.

The compounds of formula (I1) as well as their addition salts with the pharmaceutically-aceptable acids are products which are particularly interesting from the pharmacological point of view; they possess in particular remarkable antiglucocorticoid activity as is shown by the accompanying test results.

The study of the product.’ on hormone receptors has enabled progestomimetic or arti-progestomimetic, androgenic or anti-androgenic activity to be made evident.

S2S9S The compounds of formula (I1) as well as their addition salts with the pharmaceutically-aceptable acids can therefore be used as medicaments to control mainly side effects af glucocorticoids; they also permit control of disorders due to hypersecretion of glucocorticoids and especially of ageing in general and more particularly of hypertension, atherosclerosis, osteoporosis, diabetes, obesity as well as immunity depression and insomnia.

The compounds of formula (I1), as well as their addition salts with the pharmaceutically-aceptable acids, which possess anti-progestomimetic properties can be used to prepare original contraceptives; they can also be used against hormonal irregularities and, in addition, they can be of advantage in the treatment of hormone-dependent cancers.

Certain compounds of formula (I1) as well as their addition salts with the pharmaceutically-aceptable acids can also display progestomimetic properties and can thus be used in the treatment of amenorrhoea, dysmenorrhoea and luteal insufficiencies.

The compounds of formula (!'), as well as their addition salts with the pharmaceutically-aceptable acids, which display anti-androgenic properties, can be used in the treatment of hypertrophia and of cancer of the prostate gland, of hyperandrogenia, of anaemia, of hirsutism and of acne.

The subject of the invention is, therefore, as medicaments, the compounds of formula (I1) which are pharmaceutically-aceptable, that is to say non-toxic at the doses used, as well as their addition salts with the pharmaceutically-aceptable acids.

The usual dosage varies depending upon the complaint to be treated and the route of administration; it can vary, for example, from 10 mg to 1 g and preferably from 100 mg to 1 g per day in the adult by oral route.

The new compounds of formula (X') and their salts, as defined above, can be used to prepare pharmaceutical compositions containing, as active principle, one at least of the said compounds.

The compounds of formula (I1) and their salts are used by digestive, parenteral or local route. They can be prescribed in the form of plain or sugar-coated compressed tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, cream and gels which are prepared according to the usual methods.

The active principle or principles can be incorporated in excipients usually employed in pharmaceutical compositions such as talc, gum arabic, lactose, starch, S2595 magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.

The subject of the invention is, therefore, the pharmaceutical compositions containing as active principle at least one compound of formula (Τ').

The subject of the invention is also a process for preparing the compounds of formula (I'), wherein a compound of general formula (II): I OH in which K represents a ketone group blocked in the form of a ketal, thioketal, oxime or methyloxime, and Rp R2 a11'3· x keep the same meaning as before, is subjected to the action of a dehydrating agent capable of releasing the ketone function, to obtain a compound of formula (I1 o· which is subjected, if necessary, either to the action of a ketalisation agent to obtain 10 the compound of formula (I'g) in which the ketone function at position 5 is blocked in the form of a ketal: ketal X or to the action of the free hydroxylamine NKgOH or the hydroxylamine blocked in the form of NHg-O-alkj in which alk^ keeps its previous meaning, to obtain the compound of formula (I'q)s in which R represents a hydrogen atom or a group alkj, or to the action of a reducing agent capable of reducing selectively the ketone function obtain the compound of formula (Ι’θ): S2595 which is subjected, if necessary, either to the action of an etherification agent capable of introducing the radical alk^ to obtain a compound of formula or to the action of an esterification agent capable of introducing the group CO alkg in which alkg keeps its previous meaning, to obtain a compound of formula (I'p): 52596 or, which compound of formula (1'^) is converted, if necessary, according to the known methods, into a derivative for which C=A represents a group CH2 and which compound of formula (1'^), (£'3), (I'q), (T'p) U'e). or (I'p) » if necessary, is subjected to the action of an acid to obtain a salt or to the action of an oxidizing agent to obtain either, if the radical R^ contains a nitrogen atom, a derivative containing at position 11β a radical of which the nitrogen atom is oxidised and in which the radicalsB and C form possibly an epoxide bridge, or, if the radical R^ does not contain a nitrogen atom, a derivative in which the radicals B and C form an epoxide bridge and in which compound at the same time the radical R^ contains an oxidised nitrogen atom and B and C together form an epoxide bridge which, if necessary, is reduced selectively at the level of the oxidised nitrogen atom contained in the radical and which, if necessary, is subjected to the action of an acid to obtain a salt.

The subject of the invention is, more particularly, a process as defined before for preparing the products of formula (I') for which X represents the residue of a ring of formula: in which R2, and dotted line at position 16-17 are defined as before..

In a preferred method of carrying out the process, the dehydration agent capable of releasing the ketone function is a sulphonic resin (acid form), for example a commercial sulphonic resin with a polystyrene support or with a styrene / divinylhenzene polymer support; but a mineral acid such as hydrochloric acid or sulphuric acid in a lower alkanol or perchloric acid in acetic acid, or a sulphonic acrid such as paratoluene sulphonic acid can also be used.

The ketalisation agent is preferably an alcohol or a dialcohol in the presence of an organic acid such as, for example, oxalic acid or paratoluene sulphonic acid.

The agent for reducing the ketone function is preferably an alkali metal hydride. (See on this subject the article by E. R. Valkis in Chemical Society Reviews 1976, Vol. 5, no 1, page 23.) The etherification agent is preferably an alkyl halide in the presence of a base.

The esterification agent is preferably a caTboxylic acid derivative, for example a chloride or an anhydride, in the presence of a base such as pyridine.

It is self evident that when one of the radicals R^ or R^ of the products of formula (I1) obtained previously represents a radical OH, the said radical OH of these products of formula (I1) can he subjected to the action of an etherification or esterification agent.

This etherification or esterification agent is preferably one of those which have been mentioned above.

When or Rft representsan acyloxy radical at position 17, this acyloxy group can possibly be saponified. The saponification agent used is preferably a base such as sodium hydroxide, potassium hydroxide, potassium amide or potassium tert-butylate, the saponification reaction being carried out preferably in a lower alcohol such as methanol or ethanol, it can also be lithium acetylide in ethylene diamine.

The oxydising agent is preferably a peracid such as metachloroperbenzoic acid, peracetic acid or perphthalic acid or else hydrogen peroxide alone or in the presence of hexachloro- or hexafluoroacetone. When it is desired to Obtain a .compound in which only the nitrogen atom of the radical R^ is oxidised, one equivalent of oxidising agent is used.i When it is desired to obtain a compound in which, in addition, B and C form an epoxide bridge, two equivalents of oxidising agent are used.

The agent for selectively reducing the N-oxide function is preferably triphenylphosphine and work can be carried out, for example, in acetic acid.

The subject of the invention is also a; preparation process as defined before, characterised in that the starting product of formula (II) is prepared by subjecting a compound, of formula (III):: (m) to the action of a compound selected from the group constituted by the compounds formula (R^)g Cu Li, of formula R^Hg Kai and of formula R^ Li, in which Rp keeps the same meaning as before and Hal represents a halogen atom, if necessary, in the presence of cuprous halide, to obtain the corresponding compound.of formula (II).

In a preferred method of carrying out the process of the invention: - the reaction takes place at ambient temperature, - the compound of formula (III) is subjected to the action of a compound of formula R^Mg Hal in the presence of copper salts.

The subject of the invention is also a preparation process as defined before, characterised in that the starting product, responding to the formula (II') : OH in which Rp R2 and E are defined as before, H'^ represents a hydroxy radical or a radical 0R„ in which R„ represents c c the residue alk^ of an ether group or COalk^ of an ester 5 group, alk^ and alk^ being defined as before and R1^ represents the hydrogen atom or an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, is prepared by subjecting a compound of formula (IV): (IV) to the action of a compound, selected, from the group constituted by the compounds of formula (R^)^ Cu Li) of formula R^MgHal and. of formula R^Li, in which R^ and Hal are defined as before, if necessary in the presence of copper halide, to obtain the compound of formula (V): OH which is subjected either to the action of a reducing agent, to obtain the corresponding 17-hydroxy compound or to the action of an appropriate magnesium derivative, to obtain the corresponding 17a-substituted 17p-hydroxy compound or to the action of an organometallic derivative such as a lithium derivative or a potassium derivative, to obtain the corresponding 17&-substituted 173-hydroxy compound, or a) to the action of a cyanidation agent, to obtain the corresponding 178-oyano 17«-hydroxy compound, of which the hydroxy function is protected, then b) to the action of an organometallic derivative as described before, to obtain the corresponding 17"-substituted 88505 17p-hydroxy compound and in that, if necessary, one or other of the 17-hydroxy compounds obtained above is subjected to the action of an esterification or etherification agent and that, if necessary, one or other of the 17-substituted compounds obtained above in which the substituent at position 17 contains a triple bond, is subjected to the action of a reducing agent, to obtain the corresponding ethylenic derivative.

In a preferred method of carrying out the process of the invention, the reaction of the compound (IV) with the compound R^ Mg Hal, (R^)2 Cu Li or R-j, Li is carried out under the conditions already described before.

The different reagents which are reacted with the compound of formula (V) are well known in the chemistry of the steroids. The experimental part hereinafter describes some of the reactions with the compound of formula (V).

The compounds of formula (II) as well as the compounds of formula (V) are new chemical products and the subject of the invention is the compounds of formula (II) as well as the compounds of formula (V) as new chemical products.

The subject of the invention is, more particularly, as new chemical products: - llE3-[4-(trimethylsilyl) phenyl] 3,5-[l,2-ethane diyl bis (oxy)J 17a-(prop-l-ynyl) estr-9-en 5c,17£-diol, - 11β-(«-pyridyl) 3,3-[l,2-ethane diyl bis (oxy)] 17 - llp-[3-(N,N-d.imethylamino) propyl] 3,3-[l,2-ethane diyl bis (oxy)] 17"-(prop-l-ynyl) estr-9-en 5",17P-diol, - 11β-ι'4—dimethylaminophenyl) 3»3"Cl,2-ethane diyl bis (oxy) ] 17a-(prop-l-ynyl) estr-9-en 5a, 17£-diol, 3,3-Cethane diyl bis (oxy)] l^-[4-(N,N-dimethylaminoethyloxy) phenyl] 17"-(prop-l-ynyl) estr-9-en 5<*, 17P-diol, - 21-chloro 3,3-Cl,2-ethane diyl bis (oxy)] llB-(4~dimethyl 10 amiaophenyl) (17°) 19-nor pregn-9-en-20-yn 5a,17B-diol and - lip-(«-dimethylaminophenyl) 3,3-(1,2-ethane diyl bis (oxy)] 17"-(prop-2-ynyl) estr-9-en 5», 17g-diol.

The subject of the invention is, of course, more particularly, the compounds of formula (II) and (V), especially the products of formulae (II) and (V) prepared in the experimental part, as new industrial products necessary for carrying out the process of the invention.

The' compounds of formula (IH) and especially, among these the compounds of formula (IV), used to prepare the compounds of formula (II) or (V) are generally-known products, which can be prepared by subjecting the corresponding Δ5(10), 9(11) compounds to the action of an agent for selectively epoxidising the double bond 5(10). Thus the ^5(10) 9(11) compounds can be subjected, for example, to the action of hydrogen peroxide used in the presence of hexachlorosce-tone or hexafluoroacetone, according to the process- described and claimed in French Patent 2,423,486. 5,5il,2-ethane diyl bis (oxy)] 17 The subject of the invention is, therefore, also this product as a new chemical product and more particularly as an intermediate product necessary for carrying out the process of the invention.

In addition to the products described in the examples which illustrate the invention without, however, limiting it, the following products constitute products which can he obtained within the scope of the present invention.

A) The products of formula : in which the substituents A, R^, R2, Rj and R^ have the following meanings. (She sign indicates that the substituent is the same as the one above).

A DiR2R3R4 0 Λ-0.CH3 OH -C=C-H 1». ‘5 1» · -CSC-CF-j It II II -csc-ch2ch3 l| II -ch2-c=c-h II II II tl -C=C-SiMe3 II II II -C=C-H OH II II -C=c-SiMe3 OHCH2CH3 OH -C=C-H · · OH -C=C-CH3 II II OH -CH2-C=C-H IICH3 -|-ch2oh H <1 II ·· II OH HO-N=(E) II OH -C=C-H It II -c=c-ch3 II II -C=C-H OH II Ii OH -CH2-CSC-H HO-N=(Z) II It OH -C=C-H 1' II II ' -C=C-CH3 II II II II -CH,-C=C-H II II -C2C-H OH 0 II OH -C3C-H · II II -C^C-CF-j ·· It -CH2-C2C-H It II II II -csc-ch2ch3 ’· n II II -C=C-C1 II II II II -C=C-SiMe3 · II It -C=C-H OH It II -C£C-SiMe3 OH AR1R2R3R4 0 i®· CH2CH3 OH -C=C-H 11 II -c=c-ch3 It · II -ch2-csc-h '· ftCH3 -C-CH.OH S 2 -H II II II -OH II -C-CH, II 3 0 -H HO-N=(E) ·' -OH -C=C-H ·· II -csc-ch3 II II II -CSC-CH2CK3 '· II ·' -CH2-CSC-H It II -C=C-H fi -OH -C-CH2OH H KO-N=(Z) II II II 11 II II tt OH -C—C-H ' II ' -C=C-CH3 II II ·' -C=C-CH2CH3 tl II -CH2-C=C-H 1 II ·· -CSC-H -OH 0 II ii II » *· OH -C=C-H II II tl It -c=c-cf3 ' '· -CSC-C1 II ir II tl -CSC-CH2CH3 '· ·· II fl -CHj-CSC-H II II ' ·' -C=C-SiMe3 II (1 — C-CH.OH II 2 0 -H 58595 AR1R2 R3R4 KO-N={£) II ch3 II OH II —C=C—K -C5C-CH3 II II II II -CH2-CSC-H at II II -CSC-H -OH HO-N=(Z) II It ' II - II '· II OH -C-C-H II It -C=C-CH3 0 II It tl -ch2-cbc-h -C=C-CH2CH3 II II If -c=c-c?3 ' II -CSC-SiMe3 -OH II -C-CH.OH tt 2 -H ·· ·' II -OH It *' If -C-CH. II 3 O -H It II . CH2CH3 OH -C=C-H II II II -C=C-CH3 ir II II II -c=c-cx tt II II tl -C5C-CH2-CH3 II II. II II -C=C-SiMe3 II '· II -CH2-C=C-H .. tl .. 0 -tt-CHjOH -H HO-N=(E) CH3 -C=C-H -OH II II II -2oh 0 -H It ·- II OH -ch2-csc-h HO-N=(Z) II II II II AR1 *2 *3R4 HO-H=(Z)CH3 -C=C-H -OH II II II -c-ch2oh -H 0 0 ;n-<0V II a · It ii -C=C-H -OH ·· ·· -- OH -CH2-C=C-H ' II II -C=C-CH2CH3 '· 1« II . -C=C-CF3 ii II II tt -C=C-H II -CSC-SiMe3 HO-N=(E) II It OH -C=C-H ' II - -CSC-CH3 II II II -CSC-CH2CH3 '· II '· -CSC-Cl II tl It -C=C-SiMe3 II II -ch2-csc-h ' •1 It -C=C-H -OH HO-N=(Z) II II - li II II OH -C=C-H II ’· ' II -CSC-CHj II It -csc-ch2-ch3 - II II 1' -csc-cl II -C=C-SiMe3 ii 0 1« It II OH -ch2-c=c-h -C3C-H '· II II It -csc-cf3 It II II II -C2C-CH3 II II II -csc-cl AR1R2R3R4 ϋCH3 OH -CH 2-C=C-ii V It II -H II I II -C-C-H -OH η It -C-CH-OH £ 2 -H ' ii · II It II OH -C-C-H · ii II -c=c-ch3 It II II -C=C-C1 It II II II -CH2-CSC-H It n It -C=C-H -OH II II l> II ' II OH —C=C-H II It II II -c=c-cf3 <1 tt II '· -C=C-CH3 II \ II II -CH2-C=C-H It II II ZN\/O-^O>- II II It -H -C=C-K · II -ch2-csc-h · tl -C=C-H -OH .. II °^c-ch2oh II -H II II II II It II -C=C-H -OH It ’ tt -OH -C=C-H ii ii tt -c=c-ch3 II It tl ii -ch2-csc-h · CHkZXo-^°) ii -OH -C=C-H II II II II -c=c-ch3 52595 ·. 1 AR1R2R3R4 0 O^N^O-(oy ch3 -OH -CH2-CSC-H ·. II II -C=C-H -OH 11 11 °^c-ch2oh -H II 11 II II II 1« II -C=C-H OH It II OH -c=c-cf3 -· II tl OH -C=C-H «1 II II -ch2-ch=ch2 · II II ch2-csc-h II II It II 0. -CHj II It II /C-CH3 -CH3 II II OH -CH2-CN HO-N=(E) '· '· OH -C3C-H ' tl II -CSC-CH3 II II II -CSC-CH2CH3 It II II -CSC-Cl · II ' -CH2-C=C-H '· (1 II -C=C-H -OH '· It \:-ckooh 2 -H HO-N=(Z) tl II II II ' It II -C-C-H -OH M OH -C=C-H ·' -csc-ch3 II II '· II -C3C-CH2-CH3 (( It II II -CSC-Cl II tl II Ii -CH2-CSC-H 0 ' CH2CH3 II -C=c-H II If II -C=C-CH3 52585 ΛR1 *2R3R4 ΗΟ-Ν=(Ε) MegSi CH2-CH3 OH -ch2-c^c-h ΗΟ-Ν=(Ζ, -C=C-H -OH ·' II II OH -C=C-K II ιι -CSC-CH3 ιι II -CHg-CSC-H 0 -φ- ιι it -c=c-oh3 II II it J2-CH.OH Ci 2 —H II II It II ti II OH -C=C-H II II ll II -c=c-ch3 II II It II II II -CHg-C^C-K -CHg-CKaCHg ιι ιι II II -CHgCN It -C=C-H 0 -OH ιι II II v-CH-OH Z 2 -H II II II O=C-CH3 -ch3 >1 » II OH -H II II OK -C=C-H II II . II -c=c-cf3 -C=C-CH2CK3 II II II -CSC-C1 II · II II -CH2-C=C-H II II -C=C-H 0 -OH 1% II II ^C-CH-OH -H / 2 1 II0<*t-CH, -CH- X 3 3 ·» » CHgCHg OH -C=C-H ·· It It »» -CHC-CH3 ·> il II -ch2-c=c-h AR1R2 R3R4 0 pj- ^ηζ\ζ^Ν-(ο^ ch3 OH -CH2-C=C-H it li II -H tl o-®- II It II II -CH3 -CsC-H -C=C-CH3 tl II tl II II II II -C=C-CF3 -CH2-CzC-H it II II II HiCVN y . It It It -C=C-H OH II -OH -C=C»H -C=C-CH3 It It II II -C=C-CF3 II II It -CH2-C=C-K It It tl - -C=C-H -OH It II II -c=c-ch3 -OH 3) The products of formula in which R^, R^, and R^ have the following meanings : R1R2R3R4 s®- ch3 OH -CsC-H II 1» -c=c-ch3 II II II -C=C-CF3 II II II -ch2ch3 / li It -CH2-C=C-H 52585 It is also possible to prepare the epoxides corresponding to the products appearing in list A above.

Example 1; 17B-hydroxv 17g-(proo-l-ynyl) l!B-(4-pyridyl) estra-A.9-dien-3-one. 5tagg_A_2_ 3-^-β (4-Pyridyl j, t C112-ethanediyl_ bis( oxy) I I22xlEr22zlzZSZil_S5S£z2zS5_52_i2Sz^i2ii At 20° C, 100 cm^ of a solution, of 4-chloropyridinyl magnesium bromide in tetrahydrofuran (0.5 - 0.6 M solution prepared from 15 g of 4-chloropyridine and 6g of magnesium) are added to a solution containing 6.16 g of dimethyl sulphide z / copper bromide complex in 40 cm of tetrahydrofuran.

The whole is agitated for 20 minutes at ambient temperature under inert atmosphere and over 10 minutes a solution containing 3-7 g of 3,3-Cl,2-ethanediyl bis (oxy)] 5« ΙΟα-epoxy 17a-(prop-l-ynyl) estr-9(ll)-en 17β-ο1 is added. The whole is agitated for one hour at ambient temperature and poured, into a mixture of cold water and ammonium chloride. The reaction mixture is agitated for half an hour at ambient temperature and extracted with ether. The extract is washed with a saturated solution of sodium chloride, dried and concentrated to dryness under reduced pressure. 6 g are obtained of a product which is chromatographed on silica, elution being carried out with the methylene chloride / acetone mixture, 1:1 containing 1 per thousand of triethylamine. 3.15 g are thus isolated of a product which is dried under a vacuum of 0.1 mm of mercury at about 60° C. The product sought is thus obtained aD" ~52° i 1,5 (c"156 Stage B : 17P~hydroxy 17°-(prop-l-ynyl) 11β (jj—pyridyl) estra For 3 hours at ambient temperature under inert atmosphere a solution containing 2.9 g of the product prepared in Stage A, -3 14- cm of methanol and 7 car of 2N hydrochloric acid is agitated. 3 A solution containing 200 cm of ether and 90cnr of a saturated solution of sodium acid carbonate is then added.

The whole is agitated for 15 minutes at ambient temperature, decanted and extracted with ether. The extracts are washed with a saturated solution of sodium chloride then dried and concentrated to dryness under reduced pressure. 2.3 g are obtained of a product which is chromatographed on silica, elution being carried out with the methylene chloride / acetone mixture :6:4-. 1.7 g of product aieisolated and dried under pressure of 0.1 mm of mercury for 24- hours of which 8 hours are at 80° 0. The product sought is thus obtained = + 3O°5 -1° (c = 1% C3G15) In the same manner, 17P~hydroxy, 17"-(pr0p-l-ynyl) llp-(3-pyridyl) estra 4-,9-dien 3-oue ([a]D= +14° c = IX CHClj) and 178-hydroxy 17a(prop-l-ynyl) llp-(2-pyridyl) estra-4,9dian 3-one ((a]p = -2° c = 1% CHCl^) are prepared.

Example 2 : 173-hydroxy llS[3-N,N-diir.ethyl amino) propyl] 17tx-(prop-l-ynyl) estra-4,9-dien 3-one.

Stage A : lip-[3-(N,N-dimethylamino) propyl] 5,5-Cl,2-ethane ig-(pjg) jrop-l-ynyl) estr-9-en 5« 17g-diol« Over 5 minutes at 0° C, 12.35 g of dimethyl sulphide / copper bromide complex are added to 141 cm^ of 3-(N,N dimethylamino) propyl magnesium chloride (0.85 M solution 42 prepared from 42 g of chloro 3-N,N dimethylamino propane and 10.5 S of magnesium. The whole is kept under agitation for 25 minutes at 0° C and, drop by drop, 5-70 g of 3,3[l,2-ethanediyl bis (oxy)j 5« 10a epoxy 17 The whole is agitated for 15 minutes at ambient temperature then extracted with ether. The extract is washed with a saturated solution of sodium chloride, dried and concentrated to dryness under reduced pressure. 4.6 g of a product are obtained and chromatographed on silica, elution being carried out with a methylene chloride / methanol mixture (8 : 2). 2.55 g of product are isolated. [uJD = -86° - 1.5 (c * 1% in chloroform) Stage B : 178-hydroxy_11β C5-(N,H-dimethylaningl._prgpyl] ,17g iEE2EzilZ2Zi}_22SE2_ii:A2x2i®Sx2T2E2i x 2.4 g of the product prepared in Stage A, 14 cnr of 2C methanol and 7 cm^ of 2N hydrochloric acid are agitated at ambient temperature for 4 hours under inert atmosphere . 2C0 cm^ of isopropyl ether and 90 cm^ of a saturated solution of sodium acid carbonate are then added. The whole is agitated for half an hour at ambient temperature, decanted and extracted 2~ with ether. The extract is washed with a saturated solution of sodium chloride and dried. It is concentrated to dryness under reduced pressure and 1.8 g of a product are obtained and 52505 chromatographed on silica, elution being carried out with the chloroform / methanol mixture, 8:2. 1.30 g of a product are thus obtained and dried at about 30° - 40° 0 under reduced pressure of 0.1 mm of mercury. 1.25 g of product sought are thus obtained, [a]jj « -lift0 + 2.5° (c = 1% GHCl^). Example 3 t llB-Cft-(N.N-dimethyl amino ethyloxy) phenyl] 17Shydroxy 17s-(prop-l-ynyl) estra ft.9-dien-3-one, Stage_A_£^2i5;ethane-diyl_bis^oxy2wllg;Cft;£NAH-dimethyl_amino a) magnesium derivative of ft-(N,N-dimethylamino ethyloxy) bromobenzene.

Drop by drop over ft5 minutes a solution containing 2ft g of "-(Ν,Ν-dimethylamino ethyloxy) bromobenzene in 90 cm^ of anhydrous tetrahydrofuran is introduced. The reaction is catalysed by the addition of 0.2 cnA of 1,2-dibromoethane. When the introduction is finished, the whole is agitated again for 1 hour at 25° 0. A 0.7 H solution is thus obtained and used as it is. b) condensation.

The solution prepared above is added to a solution containing S.16 g of dimethyl sulphide / copper bromide complex in 20 cnr of tetrahydrofuran. The whole is agitated for 20 minutes at ambient temperature and, drop by drop, over a few minutes, 3.7 g of 3,3Cl,2-(ethanediyl bis (oxy)] ’ 5", 10 ["3d = -44° + 1.5° (c = 1% CHClj) Stage_B_i!-lIS£4-^NiN;dimethjlamino_ethylo^}_2henyl]_12^x 9.5 cm'’ of 2N hydrochloric acid are added to a solution containing 4.5 g of the product prepared in Stage A in 20 cm^ of methanol. The solution is kept under agitation for 2 hours x x at ambient temperature and 260 cur of ether and 110 cm of a saturated solution of sodium acid carbonate are added.

The whole is kept under agitation, for 15 minutes at ambient temperature, decanted, and extracted with ether. The extract is dried and concentrated to dryness under reduced pressure. 3,5 g of a product are obtained and chromatographed on silica, elution being carried out with the methylene chloride / methanol mixture (92.5 : 7-5). 1.8 g of amorphous expected product are thus obtained. = + 71° (c-1% CHOlj) Example « : 17B-hydroxy 116-(Z|—dimethylamino -phenyl) 17°(prop-l-ynyl) estra «.9-dien-3-one, Stage A ; ^llg-(«-diaethylaminq..phenyl) 3,3(l,2-ethanediyl 5iS_i22Z}2_i22iE£22xizZSZi}_®SSl_2x®Sz55il2fiz^i2l±_ A solution containing 38 m.moles of p-dimethylamino phenyl magnesium bromide in tetrahydrofuran is added to a suspension containing «.1 g of copper bromide / dimethyl sulphide complex in 20 cm^ of tetrahydrofuran. 2.«5 g of 5,3-Cl,2-ethanediyl bis (oxy)] 5°, 10° epoxy 17°-(prop10 1-ynyl) estr 9(11) en 17β-ο1 in solution in tetrahydrofuran are then added. The reaction mixture is kept under agitation for 10 minutes and hydrolysed with 50 cm of a saturated solution of ammonium chloride. The whole is decanted and extracted with ether and the organic phase is washed with water and dried. The solvents are evaporated under reduced pressure and 11 g of crude product sought are obtained.and chromatographed on silica, elution being carried out· with the cyclohexane / ethyl acetate mixture, 6:40. 1,8 g of the product sought (11β) and 750 mg of the product 11a are thus obtained. The products are recristallised from isopropyl ether and ethyl acetate.

Kit. = 210° C [«]_ = -66°5 (l% OHCl,). u p 52585 Sta£e_3_£_12g-hydro^_llg-£^iT^h/i2i2£-2__2ί)22Σΐ2_ΧΖ2ζ£££22Ζ ix2HZi}-22£2Sziii2z^i22i3l222± cm^ of a solution of concentrated hydrochloric acid are added to a solution containing 1.53 g of the product z prepared in Stage A in 60 car of methanol. The whole is agitated for 30 minutes at ambient temperature and 150 cm^ of ether are added, then 50 cm^ of a N aqueous solution of sodium hydroxide. The reaction medium is agitated for 15 minutes and decanted and the organic phase is dried.

The solvents are evaporated under reduced pressure and 1.4 g of crude product are obtained and purified on silica, elution being carried out with the cyclohexane / ethyl acetate mixture (7:3). O.932gof the product sought are obtained with M. Pt. = 150° 0 [a]D » + 138.5° (c = 0.5% OHClj) Example 5 ·· 17β-hydroxy 17a-(prop-l-ynyl) HB[(4-trimethylsilyl) phenyl] estra-4.9-dien-5-one. 3tage_A_£_llg[^4-trimethylsilyl)ghenyl].3A2Xij.2-ethanediyl At -50° C under inert atmosphere there are added to -° 45 cm^ of a 0.65 M solution of 4-trimethylsilyl phenyl magnesium bromide in tetrahydrofuran, 2C0 mg of copper chloride then, drop by drop, the temperature being kept at -20° C, a solution of 3.3 g of 3,3-ul,2-ethanediyl bis (oxy)] 5a, ΙΟα-epoxy 17"-(prop-l-ynyl) estr 9(H)-en 17β-ο1 in 25 cm^ of tetrahydrofuran. After one hour the whole is hydrolysed by means of an aqueous solution of ammonium chloride, extracted with ether and dried and the solvents 8258S 5o "are evaporated under reduced pressure. The residue is chromatographed on silica, elution being carried out with the methylene chloride / acetone mixture (94:6) containing 0.1 % of triethylamine. 2.087 g of the product sought are isolated and purified by recristaBisation from isopropyl ether then from ethyl acetate, ti.Pt = 226° C [a]D = -50° + 1.5° (c = 0.9% CHClj) Stage B : 17p-hydroxyii17"-(proE-l-^yl). llgiC^trimethylsilyl) 1.7 g of Redex sulphonic resin are added to a solution containing 1.68 g of the product prepared in Stage A in x o cur of boiling 90 alcohol. The whole is heated to refux for 50 minutes, the resin is separated and rinsed with methylene chloride and the filtrate is evaporated under reduced pressure. The residue thus obtained is taken up with methylene chloride and dried and the solvent is driven off under reduced pressure. The residue obtained is chromatographed on’silica, elution being carried out with the benzene / ethyl acetate mixture (85:15). 1.217 g of the product sought are thus obtained, melting at 212° 0. (α]ρ = + 94° (c = 0.9% CHC15) In the same manner, 17lS-hydroxy-i7‘*"(pi"op-l-ynyl) 1l£-r(5-trimethylsilyl) phenyl] estra-4,9-dien-5-one was prepared.

M - + 52.5° 4 2° (c = 1% CEC1,).

Preparation : 3.5-(1.2-ethanediyl bis (oxy)] 17a-(prop-l-ynyl) estr- 9(ll)-en 5.10-epoxy 178-ol.

Stage A: 5i5-Cl,2-ethangdiyl bis_(oxy) j^g-^orop-l-ynyl) _estra 5(10) 9(11), -_dien 17g-ol.

Under agitation, 207 cm^ of a 1.15% solution of ethyl magnesium 48 52595 , bromide in tetrahydrofuran are cooled to 0° C and propyne gas previously dried on calcium chloride is bubbled in for 1 hour 30 minutes at 0° C. The whole is allowed to return to ambient temperature and agitated again for 1 hour, the bubbling-in being maintained. Then at 20*25° 0 over half an hour a solution containing 30 g of 3,3-[l,2-ethanediyl bis (oxy)3 estra 5(10) 9(ll)-difin 17-one in 120 cm^ of anhydrous tetrahydrofuran and one drop of anhydrous triethylamine are added. The whole is agitated at ambient temperature for two hours and poured into a mixture of distilled water, ammonium chloride and ice. The whole is agitated and extracted three times with ethyl ether. The organic phase is washed with water, dried and concentrated under reduced pressure.

The residue is dried under vacuum. 35.25 g of the product sought are obtained.

N. K.B. Spectrum CLClg ppm O. 83 H of the methyl at 18 1.85 H of the methyl at cs c CH^ .65 H of the carbon at 11 H of the ethylene ketal §ESS2_2_i_2i2r£ii2"e5hZienedioxj_bis_(ox2}]_172-£2ro2;l2ynyl) Under agitation and bubbling-in of nitrogen, 30 g of the product prepared in Stage A are introduced into 150 x o cm of methylene chloride. The whole is cooled to 0 C then, all at once, 1.8 cur of hexafluoroacetone sesquihydrate 3 are added then, under agitation, 4.35 cur of 85% hydrogen peroxide. The reaction mixture is kept under agitation and hubbling-in of nitrogen at 0° 0 for 72 hours. The reaction solution is then poured into a mixture containing 250 g of ice and 500 cm^ of 0.2N sodium thiosulphate. The whole is agitated for a few moments then extracted with methylene chloride. The organic phase is washed with distilled water, dried on sodium sulphate in the presence of pyridine, then concentrated under reduced pressure. The residue is dried under reduced pressure. 31.6 g of a product, are obtained and chromatographed on silica, eluant; benzene / ethyl acetate, 90-10 . The product sought is thus obtained. HKR Spectrum CDCl^ ppm 0.82 H of the methyl at 18 1.83 H of the methyl of the radical C - C -OHj 6.1 Hof the carbon at 11 3.92 ’ H of the ketal 2° Example 6 ; 17S-ethynyl 17e-hydroxy llB-(4-dimethylaminophenyl) estra 4,9-dien 3-one, Stage A ; 3,3-d.imethoxy 5«-17a^hydroxy ll§-(4-^dimethylaminophenyll_17B-ethynyl estr-9-ene.

Under inert gas 2.8 g of 3,3-dimethoxy 5a- ΙΟα-epoxy . 82585 17P-ethynyl 17 The whole is then allowed to rise egsin to ambient temperature.

To a suspension of the copper bromide / dimethyl sulphide complex (6.15g) in 30cm^ of anhydrous tetrahydrofuran are added S3 om^ of (4-dimethylaminophenyl) magnesium bromide so that the temperature remains below 28.5°. The whole is left for 30 minutes under agitation then, drop by drop, the solution obtained above is added. The whole is kept for 18 hours under agitation at ambient temperature, poured into a saturated solution of ammonium chloride, agitated for 10 minutes and extracted with chloroform, the organic phase is washed with water and dried and the solvent is evaporated.

The residue is chromatographed on silica, elution beingcarried out with the petroleum ether / ethyl acetate mixture (1:1) containing 0.5 per thousand of triethylamine and 1.28 g of product are obtained. This product is purified again by chromatography on silica, elution being carried out with the same mixture, and 0.84 g of expected product is obtained. 3tage_B_2_17^E®i^Z5Zi_i22z&Z^E22Z_iiSz£iiz2i22i2ii25iS2E225Zi2 sstra_«A2zSi2Sz5z222i 0.76 g of the product obtained in Stage A is mixed with 3 cur of methanol and 1.6 cur of 2ΪΓ hydrochloric acid. The mixture is agitated for an hour and a half then poured into a saturated aqueous solution of sodium bicarbonate and extracted with chloroform, the organic phase is dried and the solvent is evaporated. G.76 g of crude product is obtained and chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1) then with the ethyl ether / petroleum ether mixture (3:1). 0.435 g of expected product is obtained, which is crystallised from isopropyl ether.

M.Pt. = 142° C [D= + 235.5° i 4/5° (c = 0.45% chloroform) The starting product of Stage A was prepared as follows: Stage a : 3,3-dimethoxy 17°-hydroxy 17 (3-ethynyl estra 5(10) (ll)diene.

A mixture of 16.8 g of 3,3-dimethoxy 17P-hydroxy 17°20 -ethynyl estra 5 (10) 9 (H) diene, 175 cm^ of anhydrous tetrahydrofuran and 4.35 g of lithium bromide is agitated for minutes at ambient temperature then cooled to - 60° 0 and 3 cm of a 1.35M solution of butyllithium in hexane are added. The whole is left for 30 minutes under agitation then 3.9 cm^ 52585 s of methane sulphonyl chloride are added and the whole is left for 1 hour at -60° C under agitation. It is then poured into 500 cm^ of a saturated aqueous solution of ammonium chloride, agitated for 10 minutes and extracted with methylene chloride x the organic phase is dried, 2.5 ear of pyridine are added then the whole is evaporated to dryness under reduced pressure at 0° C. 75 cm^ of tetrahydrofuran are added to the residue obtained then 12.5 cm^ of water containing 0.75 g of silver nitrate. The whole is kept for 15 hours at -30° C, then for X 4- hours at ambient temperature. It is poured into 500 cm of a half-saturated aqueous solution of ammonium chloride, containing 5 g of sodium cyanide. The whole is agitated for 30 minutes at 20° C, extracted with chloroform, washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture(9:l). 3 g of expected product are obtained, K. Pt. a? 150° C [D = + 125 £ 2.5° (c = V/a chloroform) Stage b : 3,3-dimethoxy 5®-10<*-epoxy 17P-ethynyl 17a-hydroxy estr-9(H)-ene.

X 2.6 g of the product obtained in Stage a, 12 cr of methylene chloride and one drop of pyridine are mixed. The 0 X mixture is cooled to 0 C, and 0.12 cur of hexachloroacetone and 0.65 cm^ of hydrogen peroxide (200 volumes) are added.

After one hour under agitation, 13 cm of chloroform are added then the agitation is continued for 18 hours. The whole is poured into 100 cnr of a saturated solution of sodium thiosulphate, agitated for 10 minutes and extracted with chloroform, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. 2.8 g of expected product are obtained, which is used as it is for the following stage. (The product contains a small proportion of β epoxide).

Example 7 : 17B-hydroxy 17a-Phenyl llB(4-dimethylaminophenyl) estra 4,9-dien-3-one.

Stage A: 3.5-Cl,2-ethane diyl bis (οχ7)]^11^-;(4-άίπ6^ηγΐ3πιΐηοphenyl) estr-9-ene 5a-hydroxy 17-one. a) 22®22222ΐ22-2--5-2_22£222Ϊ22_έ2£ΪΥ2ΪϊΣ2Λ Under inert gas 29 g of magnesium turnings and 50 cur of anhydrous tetrahydrofuran are mixed. Over two and a half hours, the temperature being kept at 35° 0 - 5° C, is introduced a mixture of 200 g of 4-dimethylamino bromo benzene · in 950 cm7 of anhydrous tetrahydrofuran. A C.8 M solution of expected magnesium derivative is thus obtained. b) addition of the magngsium derivative.

Under inert gas 25 g of 3,3-Cl,2-ethane diyl bis (oxy)] 5°-10a-epoxy estr-9(ll)-en 17-one, 500 cm^ of anhydrous tetrahydrofuran and 0.757 g of copper chloride are mixed. The mixture is cooled to 0° to +5° C and , drop by drop, over 1 hour 15 minutes, there are added 284 cm^ of the solution of magnesium derivative prepared above. The whole is then agitated for 15 minutes, poured into a saturated solution of ammonium chloride and extracted with ethyl acetate and the organic phase is washed with a saturated solution of ammonium chloride then with a saturated solution of sodium chloride. The organic phase is dried and evaporated to dryness under reduced pressure. 46 g of crude product are obtained and chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1;1) containing 1 per thousand of triethylamine and 17.76 g of expected product are obtained. M. Pt. » 178° 0.

The impure fractions of product obtained are again chromatographed on silica, elution being carried out with the petroleum ether / acetone mixture (8s2) containing 1 per thousand of triethylamine. 6.35 g of expected product are again obtained. H.Ft. = 176° C. The product thus obtained is used as it is for the following stage.

Stage B J.-gj^-Elig-ethane^iyl^bis^offi}] Over 30 minutes at +25° C there is added to a solution of 33.3 cm^ of phenyllithium (1.5 H), a solution of 4.51 g of the product obtained in Stage A in 45.1 cm of anhydrous tetrahydrofuran. The whole is agitated for 4 hours at ambient temperature, poured into a saturated aqueous solution of ammonium chloride and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and Ιώβ solvent issevaporated.. 5.6 g of crude product are obtained and chromatographed on silica, elution being carried out with the methylene chloride / acetone mixture (9:1) containing 1 per thousand, of triethylamine. 1.16 g of expected product are obtained and crystallised from the methylene chloride / isopropyl ether mixture.

K.Pt. = 240° C = +53° - 2.5° (c = 0.5% chloroform) Stage 0 .: 17g-hydroxy_17a-phenyl, llg—(4-dimethylaminorib.enyl) estra^j^-dien-^one..

Under inert gas 1.5 g of the product obtained in Stage 3 x are mixed'into 4-5 cm of methanol. The mixture is cooled to 0 to +5° 0 and 3 cm^ of 2N hydrochloric acid are introduced. The whole is agitated for 1 hour at 0° to +5° C, then 90 cm^ of ether and 90 cm^ of a 0.25 H aqueous solution of sodium bicarbonate are added. The whole is agitated for 5 minutes, decanted and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. 1.30 g of product are obtained and purified by chromatography on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1). 0.93 g of expected product is obtained and crystallised from the methylene chloride / isopropyl ether mixture.

H.Pt. = 226° C EajD = +151.5° (c = 0.4% chloroform).

The starting product of Stage A was prepared as follows. 11.18 g of 3,3-Cl,2-ethane diyl bis (oxy)] estr-5 (10) (11) dien-17-one and 56 cm^ of methylene chloride are mixed two drops of pyridine are added, the whole is cooled to 0° C S2595 and 4.3 cm^ of hexafluoroacetone sesquihydrate are introduced then 1.6 cm^ of 85% hydrogen peroxide are added. The whole is kept under agitation and under inert gas at 0° C for 25 hours. It is then poured into a mixture containing 200 cm^ of 0.5 K solution of sodium thiosulphate and 200 g of ice.

The whole is kept for 30 minutes under agitation then extracted with methylene chloride containing a trace of pyridine. The organic phase is washed with water and dried and the solvent is evaporated. 11.4 g of expected product are obtained, which is used as it is for the following stage.

Example 8 : llg-(4-dimethylaminophenyl) 176-hydroxy 25-methyl (17°) 19.21-dinorchola-4.9,23-trien-2O-yn-5-one, Stage A ; .^g-Cl^g-^ethane diyl .his (oxy) i]_116-(4-dlmethylaminophenyl) 23-methyl (17q).^193,21-dinorchqlay9t25-dien-20-yn -5517g-diol.

Under inert gas 4,5 g of potassium tert-butylate are' mixed with 9C cm^ of anhydrous tetrahydrofuran. The mixture is cooled to -10° C and 10.61 cm^ off 2-methyl 1-buten 3-yne are added. The whole is agitated for 15 minutes at -10° C, then, over 15 minutes, a solution of 4.5 g of product obtained in Stage A of Example 7 in 4-5 cm of anhydrous tetrahydrofuran is added. The whole is agitated for 30 minutes at - 10° C then for 4 hours at 0 to +5° 0. It is poured into 500 cm^ of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate and the organic phase is washed 82895 with, a saturated, aqueous solution of? sodium chloride, dried and evaporated to dryness. 5·56 g of crude expected product are obtained. M. Pt. »205° C.

The product is used as it is for the rest of the synthesis.

The crude product is chromatographed on silica, elution being carried out with the methylene chloride / ethyl acetate mixture (9:1) containing 1 per thousand of triethylamine, then recrystalised from ethyl acetate, melting at 215° C.

Stage 3 : 118-(4-dimethylaminophenyl) 178-hydroxy_23-mgthyl 1° (17°) 19,21-dinorchola 4,9,23-trien-20-yn-3-one.

Under inert gas 5 g of the product obtained in Stage A are mixed with 300 cm' of methanol and 10 cnr of 2N hydrochloric acid. The mixture is agitated for 15 minutes at 20° C, 300 cm^ of methylene chloride are added then 300 cm^ of a 0.25 M aqueous solution of sodium bicarbonate.

After 10 minutes under agitation, the whole is decanted and extracted with methylene chloride and the organic phase is washed with water, dried and evaporated to dryness. 4,5 g of crude expected product are obtained and chroma20 tographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1). After ί recrystallisation of the product from diisopropyl oxide i 2.01 g of expected product are obtained. j i M.Pt = 185° C ! [°)p ~ +88.5° +1.5° (c = 1% chloroform). i i S2595 .

Example 9 : HBC^-himethylaminophenyl) 17B-methoxy 23-methyl (17°) 19.21-di norchola -4.9.25-trien.-2Cyn-5-one.

Under inert gas 4.5 g of potassium tert-butylate x are mixed into 90 of anhydrous tetrahydrofuran The suspension is cooled to -10° C then, drop by drop, 10.61 of 2-methyl l-buten-3-yne are added. The whole is agitated for 15 minutes at -10° C, then, over 15 minutes, 4.5 g of the product obtained X in Stage A of Example 7 in 45 cur of anhydrous tetrahydrofuran are added. The whole is agitated for 30 minutes at -10° C, then for 4 hours at 0° to +5° 0. 7-5 cm^ of methyl iodide are then added then the whole is kept for 30 minutes under agitation in an ice bath. The mixture is then poured into 500 cm^ of 0.1 N hydrochloric acid. The whole is agitated for 30 minutes at ambient temperature and extracted with ethyl acetate and the organic phase is washed with a saturated aqueous solution of sodium bicarbonate, then with a saturated aqueous solution of sodium chloride.

It is dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the methylene chloride / ethyl acetate mixture (95:5). 2.7 g of expected product are obtained and recrystaUised from methanol. H.Pt. =105° C .

Example 10 : 21-chloro 17 B-hydroxy 116(4-dimethyl·'aminophenyl) (17") 19-nor pregna-4,9-dien-20-yn 3-one. §22£2_4_α_21ς£^12£2_2α2ΙΙα2"2Ϊ&222_^ϊςΙ_5ϊ2.£22Σ}1 llg(4-dimethylaminophenyl),(17°)l9-norpregn-9rgg 20-2η_5"Α_17βχάϊο1Λ Preparation of the lithium derivative Under inert gas 77.5 cm^ of a 1M solution of butyllithium in hexane are mixed with 310 cm^ o£ anhydrous ethyl ether. The mixure is cooled to 0 to *5° C and, over 45 minutes, a solution of 7 cm^ of trichlorethylene in 28 cm^ of anhydrous ethyl ether is added. The whole is agitated for 1 hour, the temperature being allowed to return to 20° C. Condensation.

The mixture obtained above is cooled to 0 to +5° C and added to it, drop by drop, over thirty minutes is a solution of 7 g of the product obtained in Stage A x of Example 7 in 70 cm of tetrahydrofuran. The whole is agitated for thirty minutes at 0 to +5° C then the temperature is allowed to return to 20° 0, the whole is poured slowly into a saturated aqueous solution of ammonium chloride, decanted and extracted with methylene I chloride, the organic phase ia washed with water and dried and the solvent is evaporated. 8.5 g of crude product are obtained (H.Pt. = 220° C) and introduced into 42.5 cm^ of diisopropyl oxide. The whole is agitated for thirty minutes and separated and 5.38 g of expected product are obtained. M.Pt. 230° C The product can be purified by chromatography on silica, elution being carried out with the benzene / ethyl acetate mixture (7:3) containing 1 per thousand of triethylamine. By dissolution of this product: in methylene chloride and the addition of diisopropyl oxide, a crystaline product is obtained melting at 240° C.

[D = -83.5° t 1.5° (o « 1% chloroform) llgO-dimethylaminophenyl) (l?aj lg-noriiprsgna-4A9-dlen-20-yn 3-pue.

Under inert gas 5.38 g of the product obtained ia the previous stage and 191.4 cm^ of 95% ethanol are mixed. 15 cm^ of 2N hydrochloric acid are added, the whole is agitated for one hour and 300 cm of methylene chloride are added then 200 cm^ of a 0,25 M aqueous solution of sodium bicarbonate. The whole is decanted and extracted with methylene chloride, the organic phase is washed with water and dried and the solvent is evaporated. 5 g of crude product are obtained and chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7:3). 3.95 g of expected product are obtained and crystallised from ethyl acetate.

H.Pt » 240° 0. [o]jj « +111° - 2° (c 1% chloroform).

Example 11 ·. 21-chloro 176-hydroxy llS-(4-dimethylaminophenyl) (17a) 19-nor pregna 4.9-dien-20-yn-3one N-oxide.

Under inert gas 1.2 g of the product obtained in Example 10 are mixed into 24 cm^ of methylene chloride. The mixture is cooled to 0 to +5° Cani a mixture of 0.54 g of metachloroperbenzoic acid (at 85%) in 10.8 cm^ of methylene chloride is added.

The whole is agitated for one hour at 0 to +5° C, poured into a 0.2 N solution of sodium thiosulphate and extracted with methylene chloride, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate then with water and dried and the solvent is?evaporated. 1.3 g of crude product are obtained. This product is purified by chromatography on silica, elution being carried out with the methylene chloride / methanol mixture (7:3). 1.15 g of expected product are obtained. [α]^ " +47.5° i 2.5° (e = 0.7 chloroform).

Example 12 : 21-chloro 9a-10tt-epoxy 17B-hydroxy lie(4-dimethylaminophenyl) (17°) 19-nor pregn-4—en-20yn-3-one U-oxide. 1.18 g of product obtained in Example 10 are dissolved in 23.6 cm^ of methylene chloride, the solution is cooled to 0° to +5° C and, over 15 minutes, a mixture of 1.17 g of metachloroperbenzoic acid (at 85%) in 23.4- em^ of meth lene chloride is added. The whole is agitated for 2 hours at 20° C, 0.117 g of metachloroperbenzoic are added again the whole is agitated again for one hour, the mixture is poured into a 0.2 H solution of sodium thiosulphate and extracted with methylene chloride, and the organic phase is washed with a saturated aqueous solution of sodium bicarbonate then with water, dried and evaporated to dryness. 1.14- g of crude product are obtained. K.Pt. 220° 0.

The' product is purified by chromatography on silica, elution being carried out with the methylene chloride / methanol mixture (8:2) and 1 g of expected product is obtained. M.Pt. = 270° C [a]D = +39.5° - 2.5° (c = 0.5% chloroform).

Example 13 : 21-chloro 9«-lQ°-epoxy 17B-hydroxy llB-(4-dimethylaminophenyl) (17&) 19-nor pregn-425 -en-20-vn-3-one.

Under inert gas 0.63 g of the product obtained x in Example 12 is mixed with 6.3 car of acetic acid. 0.34 g of triphenylphosphine is added, the whole is agitated for 45 minutes at ambient temperature, poured into water and extracted with methylene chloride, the organic phase is washed with water and dried and the solvent is evaporated. 0.9 g of product is obtained and chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1). The product thus obtained is recrystallised from a methylene chloride / isopropyl ether mixture and 0.346 g Of expected product; is obtained. H.Pt. 265° C. [a]D = +4-5° - 2° (c » 0.8% chloroform) Example 14 : 17B-hydroxy 118-(4-dimethylaminonhenyl) 21-phenyl (17°) 19-nor-pregna-4.9-dien-20-yn-5-one, Stage A.: 21-phenyl_315-[l,2-ethane diyl bis (oxy)] lIB-(4-dimethylaminophenyl) 5a-17g-dlhydroxy (17;) Under inert gas 4,17 g of potassium tert-butylate are mixed into 83 cm^ of anhydrous tetrahydrofuran.

The mixture is agitated for 5 minutes then cooled to -10° C and, drop by drop, 4.,5 cm^ of phenyl acetylene are added. The suspension is agitated for 5 minutes then, drop by drop at -10° C, a solution of 4-.17 g of product obtained in Stage A of Example 7 in 41 cm^ of anhydrous tetrahydrofuran is added. At the end of the introduction the temperature is brought to 0° C then after 1 hour the mixture is poured into a saturated solution of ammonium chloride. The whole is extracted with ether, the organic phase is; washed with the aid of a saturated aqueous solution of sodium chloride, dried and concentrated to dryness and 4.7 g of product are obtained and chromatographed on silica, elution being carried out with the methylene chlorifle / acetone mixture (95s5)· 5-71 g of expected product are obtained. M.Ft. » 168° C ["JD= -119.5°- 2° (c « 1% chloroform).

Stage B ; 17P-hydroxy-llg-(4-?dimgthylaninophenyl) 21ζΕ^®5Σ·^_ϋ2Ξ2-22ζ2£ΓζΕ£25ΕΕζίΪ4.2ζ^ΐΕ5ζ22ΣΣ5ζ2ζΕδΕΛ 3.49 g of product obtained as described in the previous stage are dissolved in 68 cur of methanol, z then 6.3 cm of 2N hydrochloric acid are added.After thirty minutes under agitation, the whole is poured into a mixture of 180 cm^ of ethyl ether and 90 crn^ of a 0.25 M solution of sodium bicarbonate. The whole is agitated for five minutes, decanted and extracted with ether and the organic phases are washed with a 0.25 M solution of sodium bicarbonate then with a saturated solution of sodium chloride. They are dried, the solvent is evaporated and 4.35 g of product are obtained and purified by chromatography on silica, 2595 elution being carried out with the methylene chloride / acetone mixture (95:5) 2.13 g of expected product are obtained after crystallisation from isopropyl ether. [a]p = +22.5° - 1° (c = 1% chloroform).

Example 15 : 17S-hydroxy HS-(4-dimethylaminophenyl) 17«(propa-l,2-dienyl) estra-4.9-dien-3-one, Stage_A_£_llg;£4;dimethylaminoghenjl)_3A2xClA2-ethane diyl .bis^oxy)) 17 Into 50 cm of anhydrous tetrahydrofuran at 0 to +5° C is bubbled allene until absorbtion of 2,1 g.

The whole is cooled to -70° C and, over 15 minutes, X 23.9 cnr of a 1.3 M solution of butyllithium in hexane are added. The mixture obtained is agitated for 15 minutes at -70° C.

Condensation To the solution of lithium derivative obtained above is added, at -70° C over 25 minutes, a solution of 3.5g of the product obtained in Stage A of Example 7 in 35 cm? of anhydrous tetrahydrofuran. The whole is agitated for one hour at -70° C and poured slowly into a chilled saturated aqueous solution of ammonium chloride. The whole is extracted with ether, the organic phase is washed 82595 .· with a saturated solution of sodium chloride and dried and the solvent is evaporated. 3.4 g of product are obtained and chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1) containing one per thousand of triethylamine. There are thus isolated: a) 1.73 s of 17®-(propa-l,2-dienyl) isomer M.Pt. = 178° 0 (D - -32° - 2° (c * 0.7% chloroform); b) 1.5 g of 17 M.Pt. - 150° C [D - -15° -2° (c * 0.9% chloroform).

Stage B : 17p-hydroxy_118-(4-dimethylamlnophenyl)_17°(propa-1,2-dienyl) estra-4^9-dien-^-one.

Under inert gas 1.73 g of 17°-(propa-l,2-dienyl) isomer obtained in Stage A, 51.8 cnr5 of 95% ethanol and 3.5 cm^ of 2N hydrochloric acid are mixed. The o 3 mixture is agitated at 20 0 for one hour, 50 cnr of methylene chloride are added then 50 cm of a 0.25 M solution of sodium bicarbonate; the whole is decanted, extracted with methylene chloride, washed with water and dried and the solvent is evaporated. 1.51 g of product are obtained and dissolved in 10 cm^ of methylene chloride with heating. To this are added z cnr of isopropyl ether and the whole is concentrated and left to stand. 1.23 g of expected product are thus isolated and crystallised again from the methylene chloride / isopropyl ether mixture. Finally 1.11 g of expected product are obtained. M.Pt. « 228° C. [α]^ > +139.5° - 3° (c = 0.8% chloroform).

Example 16 : 176-hydroxy 118-(4-aimethylaminophenyl·) 17a-(prop-2-ynyl) astra-4.9-dien-3-one. 0.94 g of 17"-(prop-2-ynyl) isomer obtained in Stage A of Example 15, 28.2 om^ of 95% ethanol and 2 cm^ of 21T hydrochloric acid are .mixed. The mixture is agitated at 0 2 C for one hour, 50 cnr of methylene chloride and 2 cnr of a 0.25 M solution of sodium bicarbonate are added and the whole is agitated for 5 minutes, decanted and extracted with methylene chloride. The organic phase is washed with water and dried and the solvent is: evaporated The product obtained is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1). 0.42 g of amorphous expected product is thus obtained. [a] jj= +143° + 30 (c « 0.8% chloroform).

Example 17 : 17a-ethynyl 178-hydroxy lie-(4-dimethylaminophenyl estra 4,9-dien-3-one.

Stage A : 17B-cyano,118-(4-dimethylaminophenyl) 5),3-(1,220 ®2Lane_diyl_bis_£oxv2]_17a-trimethyl^sil^exy2_®2i£r2zSSz "χο1Α Under inert gas at ambient temperature, a solution of 18 m/moles of(4-dimethylaminophenyl) magnesium bromide in anhydrous tetrahydrofuran is added to a suspension of 2.05 g of copper bromide / dimethyl sulphide complex in cnr of anhydrous: tetrahydrofuran, then the whole 52595 * % is agitated, for 20 minutes and 20 cnr of anhydrous triethylamine are added. 0.95 g of l?9-cyano 17°(trimethyl siljisxy) 5,3-(1,2-ethane diyl his (oxy)] 5a- 10a-epoxy estr-9- (11) ene in solution in anhydrous tetrahydrofuran is then added, the whole is agitated for 15 hours at ambient temperature, poured into 50 cm^ of a saturated solution of ammonium chloride, decanted and extracted with ether, the organic phase is washed with water and dried and the solvent is evaporated.

The residue is purified: by chromatography on silica, elution being carried out with the benzene / ethyl acetate mixture(8:2). 1.1 g of expected product are obtained -and recrystallised, from isopropyl'.ether.

K.Pt. » 247° 0. [a]D = -12.5° (o * 1% chloroform) Stage ,Β : l^e-ethynyl 3,^thane_diyl^bis .(oxy)I z To 0.8 g of product obtained in Stage A in 8 cm7 of ethylene diamine is added 1 g of lithium acetylide / ethylene diamine complex, then the whole is kept under agitation and under inert gas at ~ 50° C for an hour and a half. It is cooled to 2C° C then poured into a solution of ammonium chloride. The whole is extracted with ether and with methylene chloride. The organic phase is dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7:3), the product obtained is reorystaRised from isopropyl ether and 0.4-5 g of expected product is obtained.

M.Pt - 199° 0. [a]^ s -4-3° £ 1.5° (c = 1% chloroform).

Stage C : lpa-ethynyl 17g-hydroxyi 11(4-dimethylaminophenyl) estra.-4t9z^^?2~^t9n^· To a solution of 0.25 g of product obtained in Stage H, in 6 cm^ of methanol is added 1 cm^ of 2N hydrochloric acid. The whole is agitated for 40 Λ minutes at 20 C, poured into water containing 2.5 cur of IN sodium hydroxide and extracted with ether, the organic phase is dried and the solvent is evaporated.

The residue is chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7s5) and 0.25 g of expected product is obtained.

Analysis : (415.54) Calculated : C% 80.92 H% 8.00 N% 3.57 Found : 80.7 8.1 3.1 i 82595 Example 18 : 17a-eth,ynyl 17g-hydroxy llB-(4-dlmethylaminophenyl) estra 4.9-dien-5-one.

Stage A : lli3-(4-dinethylaminophanyl) 5,3-Cl,2-ethane ^a-l^-dihydroxylTa-ethyriyl estr-9yene.

Under inert gas 6 g of product obtained in Stage A x of Example 7 are dissolved in 180 cm of tetrahydrofuran then 12.25 g of lithitaa acetylide / ethylene diamine complex are added. The temperature is taken to 55°0 and the whole is agitated for 4 hours, cooled, then poured into 600 cm^ of a chilled saturated solution of ammonium chloride. The whole is extracted with ether, the organic phase is washed with a saturated solution of sodium chloride and dried and the solvent is evaporated. The residue obtained is purified by chromatography on silica, elution being carried out with the benzene / ethyl acetate mixture (7:5) containing 1 per thousand of triethylamine and 4.5 g of expected product are obtained and recrystallised from the methylene chloride / diisopropyl oxide mixture. M.Pt. = 202° G. [a]D = -47.5° - 1.5° (c- 1% chloroform) §£5ge_B_£_17;3ethihyl_17B-hydrox2_llg-(4^di!nethylaminQOhenjl.) estra 4,9-dien-5-one. g of the product obtained in Stage A are mixed into 50 cm^ of 95% ethanol. To the suspension are X added 5 cm of 2N hydrochloric acid. The whole is kept under agitation for 1 hour at 20° C and 100 cm^ of ethyl 52585 ether are added then 100 cn? of a 0.25 M solution of sodium bicarbonate. The whole is decanted and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness. The residue obtained is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (6:4) and 1.52 g of expected product are isolated and recrystallised from diisopropyl oxide. M.Pt. » 172° C ("^d= +Ιθ2° - 2.5° (ο = 1% chloroform) Example 19 ·. 17E-hydroxy llB-(3-dimethylaminoph.enyl) 174-(pjop-l-ynyl) estr-4,9-d.ien-3-one.

Stage A : Ιΐβ-β-dimethylaminophenyl) 5,5-[l,2-ethang 4iZl_bis_£ox2}j_17axlEESEzIzZEZi2_EEiEz2zSSz2£izi2fiz2i2ii Under inert gas 1.46 g of magnesium and 5 om^ of anhydrous tetrahydrofuran are mixed. Over 45 minutes, the temperature being kept at about 50° 0, 1C g- of metabromodimethylaniline in 45 cm^ of anhydrous tetrahydrofuran are introduced. (The reaction was initiated by the addition of dibromomethane). The whole is kept for one hour under agitation and a 0.95 M solution ofthe expected magnesium derivative is obtained. SESSSSESEiSS Under inert gas 3.7 g of 3,3-(l,2-ethylene dioxy bis (oxy)] 17a-(prop-l-ynyl) estr-9 (11) en-5"-10a-epoxy x 17B-ol, 74 cm of anhydrous tetrahydrofuran .and 99 mg 52595 * of copper chloride are mixed. The mixture is cooled to 0 to *5° C then, over thirty minutes, 42.2 cm^ of the solution of magnesium derivative obtained above are added. The whole is agitated for thirty minutes at 0 to +5° C, poured into a saturated aqueous solution of? ammonium chloride and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chomatographed on silica, elution being carried out with the methylene chloride / acetone mixture (9:1) containing 1 per thousand of triethylamine. 3.5 g of expected product are obtained. M.Pt = 262° C. [α]β « -64° i 1.5° (c · 1% chloroform). 0.66 g of the corresponding 5βΟΗ isomer is also isolated. M.Pt. χ 210° C.

C°)D = +32.5° - 1° (c = 0.8% chloroform).

Stage_B: 17p-hydroxy llB-(3-dimgthyaminophenyl) 17aζί2Γ22ζΙζΣ2Σ^2_222?®_^4.2ζέί22ζ5ζ222Λ Under inert gas 3.3 g of the product obtained in Stage A are mixed with 100 cm^ of methanol and cooled ο 3 to 0 to +5 3 and EO'&arof 211 hydrochloric acid are added. The whole is agitated for 1 hour at 0 to +5° C 3 and 200 cm of diethyl oxide are added, then 200 car of a C.25 M solution of sodium bicarbonate. The whole is agitated for 5 minutes, decanted and extracted with diethyl oxide, the organic phase is. washed with a saturated solution of sodium chloride and dried and the solvent is evaporated. 3 g of product are obtained and chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7:3). 1.43 g of amorphous expected product are isolated.

[D = +43° - 2.5° (o 1% chloroform).

Example 20 : 176-hydroxy llB-(4-dimethylaainophenyl) 17°-(prop-l-ynyl) estra 4.9-dien-3-one N-oxide. 1-.5 g of product obtained in Example 4 are mixed x with 30 cnr of methylene chloride. The mixture is cooled to 0 to +5° G and, over 10 minutes, a solution of 0.71 g of metachloroperbenzoic acid ( at S5%) in 14.2 cm^ of methylene chloride is added. The whole is agitated at 0 to +5° 0 for 1 hour, poured into 100 cm^ of a 0.2 N solution of sodium thiosulphate, decanted and extracted with methylene chloride, the organic phase is washed with a 0.5 K solution of sodium bicarbonate and dried; and the solvent is evaporated. The residue is dissolved in 20 cm^ of methylene chloride and 20 cm^ of diisopropyl oxide are added. Crystallisation is initiated, the whole is left to stand and the crystals formed are separated and dried. 1.4 g of expected product are obtained. K.Pt. * 210° f. [alp = +73.5° - 2° (c = 1% chloroform). 82595 Example 21 ; llg-(4-dimethvlaminophenyl) 17B-hydroxy estra 4.9-dlen-3-one. g of the product obtained in Stage A of Example 7 is mixed into 20 cm^ of tetrahydrofuran containing % of water. After dissolution, 106 mg of sodium borohydride are added, the whole is agitated for 1 x hour , poured into 200 cm of water and extracted with methylene chloride, the organic phase is washed with a saturated solution of sodium chloride and dried and the solvent is evaporated. 1.3 g of 5a-17P-dihydroxy product are obtained. 0.63 g of product obtained above are introduced 2 2 into a mixture of 12 cnr of methanol and 2.4 cur of 2N hydrochloric acid. The whole is agitated for 1 hour thirty minutes at ambient temperature, poured into a solution of sodium bicarbonate and extracted with ether, the organic phase is washed with a saturated solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (6:4).

The residue is triturated in petroleum ether and separated and 0.38 g of expected product is obtained. M.Pt. = 130° C. [a]^ = +277° - 5° (c » 0.5% chloroforr). 82895 Example 22 : 178-hydroxy 116-(4-dimethylaminophenyl) 17a-(prop-2-enyl) estra 4.9-dien-3-one.

Stage A ; 5,?().,2-ethane..diyl· bis (oxy)] 116-(4-dimethylaminophenyl) 17g-(prop-2-enyl) estr-9-ene 5a-17g-diol.

Into 55.5 cm^ of a 0.7 M solution of allyl magnesium bromide in ether is introduced, under inert gas at 20° C over 15 minutes, a solution of 5.5 g of the product z obtained in Stage A of Example 7 in 35 cm of tetrahydrcfuran. The whole is agitated at 20° C for 1 hour,. poured into a saturated aqueous solution of ammonium chloride and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue obtained is dissolved in 10 cm^ of methylene- chloride, z To this are added 15 car of diisopropyl oxide and the whole is concentrated then left to stand. The crystals formed are separated, rinsed with diisopropyl oxide and dried and 2.76 g offexpected product are obtained.

M.Pt. =' 198° C.

Analysis : C51 Ν0ψ (493.69) Calculated : C% 74.42 8.78 H% 2.83 Found : 74.0 8.7 2.9 Stage_B_i 17g-hydrgxy_116-(4-diaethylaninophsnyl) 17g-g?op-2-enyl) .estra^g^dien-^-gne. 2.2 g of the product obtained in Stage A are put into suspension in 66 cm^ of ethanol, then 4-.5 cm^ of 2N hydrochloric acid are added. The whole is agitated for thirty minutes at 20° C and 132 cm^ of diethyl oxide are added, then 132 cm^ of a 0.25 M aqueous solution of sodium bicarbonate. The whole is decanted, extracted with diethyl oxide, washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7:3) the product obtained is taken up in a* mixture of 15 cm^ of diisopropyl oxide and 7.5 cm^ of methylene chloride and the whole is concentrated then left to stand. It is separated and the crystals obtained are rinsed with diisopropyl oxide and 1.365 g of expected product are obtained. K.Pt.· = 182° C [alp = +206.5° - 3° (c * 1% chloroform) Example 23 : 176-hydroxy HB-EQ—dT.N-dimethylaminomethyl) phenyl] 1742li42;ethane_diyl_bis_£oxy)]_llg-[4-£NAN; -dimethylaminomethyl}_2henyl]_17a42rop;l-ynyl)_estr;2zSSl Pregaration_of_the_magnesium_deriyativei Under inert gas 5.5 g of magnesium and 10 cm^ of anhydrous tetrahydrofuran are mixed. Over 1 hour thirty minutes, the temperature being kept at 45° _ 50° 0, 52585 42.8 g of 4-(N,N-dimethylaminomethyl) bromo benzene in 190 cnr of anhydrous tetrahydrofuran are introduced.

The reaction was Initiated by the addition of dibromoethane. After the end of the introduction, the whole is kept under agitation for 1 hour. The expected 0.85 K. solution of magnesium derivative is thus obtained'.

Addition on.to the epoxide.

Under inert gas 10 g of 3,3-[1,2-ethane diyl bis (oxy)] l?a-(prop-l-ynyl) estr-9, (ll)-en-5c-lOa-epoxy 17β-ο1, 200 cnr of anhydrous tetrahydrofuran and 0.27 g of copper chloride are mixed. The mixture is cooled to 0 to +5° C and, over one hour, 127 cm^ of the solution of magnesium derivative prepared above are introduced.

The whole is then agitated for 15 minutes, poured into a saturated aqueous solution of ammonium chloride and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the methylene chloride / methanol mixture (9:1) containing 1 per thousand of triethylamine. 10.1 g of product are obtained and crystallised by dissolution in methylene chloride and the addition of a few cn^ of methanol then of diisopropyl oxide. After concentration and keeping standing for six hours, the product obtained is separated and 7.37 g of expected product are obtained. 5258B M.Pt. = 186° C.

[D = -63° - 2.5° (c »0.5% chloroform).

E£2EZll..l22z£EE2EzilZ3Zi2_£Si£2_iLi.2l5A£E::2l2S2i Under inert gas 7.3? 5 of the product obtained in 3 Stage A are mixed into 147.4 cnr of methanol and 15 cm of 2N hydrochloric acid. The mixture is agitated at 20° C for one hour, 300 cm*5 of diethyl oxide and 3C0 cm^ of a 0.25 M aqueous solution of sodium bicarbonate are added, the whole is decanted and extracted with diethyl oxide, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The product obtained is recry stabilised by being dissolved in a mixture of diisopropyl oxide and methylene chloride, then by concentrating the solution and leaving it to stand. It is separated and the crystals formed are dried. 3.74 g of expected product are thus obtained. M.Pt. = 190° C.

Ca)jj = +84,5° - 2° (c = 0.8% chloroform).

Example 24 : 17g-hydroxy llg-(4-pyrrolidinyl phenyl) 17a-(nrop-l-ynyl) estra 4.9-dien-3-ons. Stage_A_4._3j.3EliA2Eethane_diyl_bis_£oxj) )^11^^(4^ T2irrolidinyl_2henyl2_17a-£gr22xl;^}yl)_estrE2zSSZ «zl2grdiol.

Under inert gas 4 g of magnesium and 10 cm^ of anhydrous tetrahydrofuran are mixed. Over one hour, the temperature being maintained at 45 - 50° C, 34 g of 4-pyrrolidinyl bromo benzene in 140 cm^ of anhydrous tetrahydrofuran are introduced. The reaction was initiated by the addition of dibromoethane. AIM solution of expected magnesium derivative is thus obtained. £22^2£2®5ϊ25_25_ί2_ίΙ}®_®225ϊ5®Α Under inert gas 8 g of 3,3-Cl,2-ethane diyl bis (oxy)] 5"-10a-epoxy 17"-(prop-l-ynyl) estr-9 (11) en-17P-ol, 160 cm^ of anhydrous tetrahydrofuran and 216 mg of copper chloride are mixed. The mixture is cooled to 0 to +5° C and, over one hour thirty minutes, 86.4 cnr of the solution of magnesium derivative prepared above are introduced. The whole is agitated for one hour, poured into a saturated aqueous solution of ammonium chloride and extracted with diethyl oxide, the organic phase is washed with a saturated aqueous solution of ammonium chloride then with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is purified by chromatography on silica, elution being carried out with the methylene chloride / acetone mixture (95:5) containing 1 per thousand of triethylamine. 8.3 g of expected product are thus obtained and recrystallised from a methylene chloride / isopropyl ether mixture. M.Pt. « 185° C [a]p · -6?° - 1.5° (c » 1* chloroform) l?B~hydroxy llg-(A-pyrrolidinylphenyl) 17a-(prop-l-ynyl) estra 4,9-dien-3-one. 6.4 g of product obtained in Stage A are dissolved in 128 cm^ of methanol then 13 cm^ of 2N hydrochloric acid are added. The whole is agitated at 20° C for X X one hour, then 256 cm of diethyl oxide and 256 ccr of a 0.25 M aqueous solution of sodium bicarbonate are added. The whole is decanted and extracted with diethyl oxide, the organic phase is washed with a 0.25 M aqueous solution of sodium bicarbonate, then with a; saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is C'iromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (1:1) and 5.25 g of expected product are obtained and recrystallised from a methylene chloride / diisopropyl oxide mixture.

M.Pt. > 190° C [a]D = +120° - 2.5° (c - 1.2% chloroform).

Example 25 : 17B-hydroxy 116-(4-dimethylaminophenyl) 17e-ethenyl estra 4-.9-dien-3-one, Stage A .: 52-ethane diyl bis (oxy)] 11β£itz^i52££ylaminoph3nyl2_12;x®ihenyl_estr-9xen^52;17g -4iol. g of product obtained in Stage B of Example 17 z are mixed with 60 car of anhydrous pyridine and 0.6 g of 5% palladium on calcium carbonate is added. A current of hydrogen is passed into the mixture at ambient temperature for one hour. The catalyst is separated, the filtrate is evaporated to dryness and the residue is taken up with toluene and again evaporated to dryness. 2.94 g of expected product are thus obtained, which is used as it is for the rest of the synthesis. M.Pt = 181° C. The product can be recrystallised from a methylene chloride / diisopropyl oxide mixture. H. Pt. = 182° C. [a]p = -6.5° - 2° (c = 0.7% chloroform) Stageβ3_: 17{?hydroxy llB-(4-dimethylaminophenyl) 17°^ zS£!l£2Zi_22££2_iij,2z2£22z5;S2®i Under inert gas 2.94 g of the product obtained in Stage A are mixed with 60 cm^ of methanol, then 6.2 cm^ of 2ίί hydrochloric acid are added. The solution is agitated at 20° C for one hour, 120 cm^ of ether and 120 cm^ of a 0.25 M aqueous solution of sodium bicarbon ate are added and the whole is kept under agitation 82595 for 10 minutes, decanted, and extracted with ether.

The organic phase is washed with a 0.25 M aqueous solution of sodium bicarbonate: then with a saturated aqueous solution of sodium chloride. It is dried and the solvent is evaporated. 2.65 g of product are obtained and chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (7s3), and then crystallised from a diisopropyl oxide / methylene chloride mixture. 1.51 g of expected product are finally obtained. M.Pt. 150° a [a]p +243° + 3° (c « 0.6% chloroform) Example 26 : 17E-hydroxy 116-(4-diethylaminophenyl) 17a-(prop-l-ynyl) estra 4,9-dien-3-one. §iS£2_A_i_3i5zl2:A2-ethane_diyl_bis_^02cy22_2i2z (^Igthylamlnoghenyl^lZa-^grog-l^ynyOestr-g-en «-17g-diol. 52£54tio3__-_ofi->the_magnesium_deriyatiyei Under inert gas 3.9 g of magnesium are mixed into 10 cm^ of tetrahydrofuran. Drop by drop, 34.2 g of 4-(N,N-diethylamino) bromo benzene in 110 cm^ of tetrahydrofuran are added, the temperature being kept at about 35° C. AIM solution of the expected magnesium derivative is obtained.

Condensation^ 7,4 g of 3,3-Cl,2-ethane diyl bis (oxy)] 5«- 10aepoxy 17a-(prop-l-ynyl) estr-9 (11) ene 17β-ο1 are dissolved in 150 cm^ of anhydrous tetrahydrofuran. 0.25 g of copper chloride are added. The whole is o x agitated at 0 to +5 0 under inert gas and 80 car of the solution of magnesium derivative prepared above are added slowly. The whole is kept for 17 hours under agitation at 20° C, poured into an aqueous solution of ammonium chloride and extracted with ether, the organic phase is washed with an aqueous solution of sodium bicarbonate and dried and the solvent is evaporated. The residue is made into a paste with petroleum ether then treated with active charcoal in ether and recrystallised from isopropyl ether. 4 g of expected product are thus obtained. [α]ρ = -61° - 2.5° (c 0.750 chloroform) Stage B : 17B-hydroxy llg-(4-diethylamlnophenyl) To a solution of 3.12 g of product obtained in x x Stage A in 45 car of methanol are added 8 cny of 2N hydrochloric acid and the whole is agitated at ° C under inert gas for 45 minutes. It is poured into water, neutralised by the addition of 2N sodium hydroxide, extracted with methylene chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the benzene / ethyl acetate mixture (1:1) and 82595 1.54 g of expected product are obtained. [a]D » +144.,5° - 3° (c - 0.8% chloroform) Analysis : Η?9 N02 (457.65) Calculated : 0% 81.36 H% 8.59 N% 3.06 Found : 81.7 8.8 2.09 The 4-(iT,lI-diethylamino) bromo benzene used at the start of Stage A was prepared as follows.

To a solution of 86 g of ΙΓ,Ν-diethylaniline in 400 cm^ of acetic acid are added, drop by drop, 93 g of bromine. After the end of the introduction, the whole is poured into a water / ice mixture and extracted with methylene chloride, the organic phase is washed with an aqueous solution of sodium bicarbonate and dried and the solvent is evaporated. 125 g of expected product are obtained. 3.Pt. ·. 0.6 · 97° C.

Example 27 : 178-hydroxy llE-[4-Cmethyl(3-methylbutyl) amino]phenyl] 17a-(proo-l-ynyl) estra 4,9-dien-5-on«.

Stage_A_,:_5Jx[lA2-ethane_diyl_bis_^oxy)]_llg2C4;;Cmeth2l (5-me'thylbutyl) amino] phenyl] 17a-(prop-;l-ynyl) estr-9-ene 5arl?E-dlql.

F£Sgaration_of_the_magnesium_deriyatiyeA Under inert gas 4.12 g of magnesium and 10 cm of 2 tetrahydrofuran are mixed. A few cm of N-methyl N-(3-methylbutyl) 4-bromo benzenamine in solution in tetrahydrofuran are introduced and the reaction is 2 initiated by the addition of 0.2 cur of 1,2-dibromoethane. »2595 Then over 40 minutes, the rest of the N-methyl N-(3-methylbutyl) 4-bromo benzenamine solution in anhydrous tetrahydrofuran (32..6 g in 90 cm^). is added. The whole is then aikmi. to return to ambient temperature then kept under agitation for 1 hour.

A 0.9 M solution of the expected magnesium derivative is thus obtained. 22S^2S2S£i23i g of 3,3-[l,2-ethane diyl bis (oxy) 3 5<χ-10αepoxy 17a-(prop-1-ynyl) estr-9 (11) en 178-ol are z mixed with 90 cnr of anhydrous tetrahydrofuran and' 3·77 g of copper chloride, The mixture is agitated for 20 minutes at +5° C under inert gas, then 100 cm^ of the solution of magnesium derivative prepared above are added. The mixture is then poured into an aqueous solution of ammonium chloride and extracted with ether mixed with triethylamine then with methylene, chloride mixed with triethylamine. The combined organic phases are washed with a saturated aqueous· solution of sodium chloride, dried and evaporated to dryness. 31.2 g of expected product are obtained,which is used as it is for the following stage. The product can be purified by chromatography on silic-a, elution being carried out with the methylene chloride / acetone / triethylamine mixture (96.5::4.5:0.5). (ijp · -59.5° - 2.5° (c * 0.7% chloroform).

I Stage B : l?6vhydroxy 11B-C4-Cmethyl (5-methylbutyl) amino]phenyl] 17g-(proo-l-ynyl) estra 4,9-dien-3-one. g of product obtained in Stage A are dissolved in 200 cm^ of methanol, then 52 om^ of 2Ni hydrochloric acid are added. After one hour under ’agitation,, the mixture is poured into an aqueous solution of sodium bicarbonate and extracted with ether then with methylene chloride, the combined organic phases are washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated.

The product is purified by chromatography on silica, elution being carried out with the toluene / ethyl acetate mixture (92i8) and 3.23 g of expected product are obtained. [a] = +125° - 3.5° (c = 0.6% chloroform) Analysis : N02 (485.71) Calculated: C% 81.6 8.92 N% 2.88 Found 81.4 9.0 2.7 The.amine used at the start of Stage A was prepared as follows. g of N-methyl aniline, 500 cm^ of anhydrous benzene and 81 g of anhydrous triethylamine are mixed. Drop by drop, 121 g of isoamyl bromide are added and the whole is taken to reflux for 100 hours. The mixture is filtered, the filtrate is washed with water and dried and the solvent is evaporated. The residue is distilled and 90 g of 82595 expected, product are obtained. B.Pt. 18 = 132° 0. Stage_b_£_N;metbjl_N2X3x£eth2lbut2l2_4^bromo_aniline_ g of product obtained in Stage a are mixed with 300 cm^ of acetic acid then, drop by drop, over 1 hour at about 15° C, 58 g of bromine in solution in 60 cm^ of acetic acid are added. The temperature is taken to 80° C, the whole is agitated for 8 hours then poured into iced water and extracted with methylene chloride, the organic phase is washed with a solution of sodium bicarbonate then with water aal dried and the solvent is; evaporated. The residue is distilled and 70 g of expected product are obtained. B.Pt 0.5 - 119° C.

Example 28 : ~17B-hydroxy llg-[4-(N,N-dimethylaminoethylthio) phenyl] 17a-(prop-l-ynyl) estra 4,9-dien-3-one.

Stage A : ]>,3Clj.2-;gthane diyl bis (oxy)] llg-[4iSj.iz2i52iiJZi52i222£^Zii&i22_E^2£Zil_iZ2ziE£22zizKii2 S2222£2ii22_2i_222-SaS322i25_222iZa£iy®i.

Under inert gas 2g of magnesium and 15 cm^ of anhydrous tetrahydrofuran are mixed. Then, over 45 minutes, the temperature being allowed to rise to 56° C, a solution of 20 g of 4-(11,N-dimethylaminoethyl thio) 1-bromo benzene in 40 cm^ of anhydrous tetrahydrofuran is introduced. The reaction was initiated bythe addition of 1,2-dibromoethane. The whole is then allowed: to return to ° C, then kept under agitation for 45 minutes under inert 52585 gas. A 1.05 K solution of the expected magnesium derivative is thus obtained.

Condensation Under inert gas 38 cm^ of the solution of magnesium 5 derivative obtained above is cooled to -20° C. To this are added 1.730 g of copper chloride, the whole is kept under agitation for 20 minutes, then 5 g of 3,3-[l,2yethane diyl bis (oxy)[ 5a-lOa-epoxy 17"-(prop-l-ynyl estr-9 (11) en 17β-οΙ in 50 cm^ of anhydrous tetrahydrofuran are added.

The whole is kept at 20° 0 under inert gas for 2 hours 45 minutes. The mixture is poured into 600 cm^ of iced water containing 60 g of ammonium chloride. The whole is kept under agitation for 45 minutes and decanted, the aqueous phase is extracted with diathyl oxide mixed with triethylamine, the combined organic phases’ are washed with sf saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. I'he residue is chromatographed on alumina, elution being carried opt with the methylene chloride / acetone mixture (95s5) and 10.3 g of expected product are obtained.

I,5,Spectrum.

Absorption at 3600 cm·1 (OH), 2240 cm-1 (C«C), 1705 and -»*1 *1 1670 cm (CO and conjugated CO), 1615 and 1490 cm" (aromatic bands). 52585 Stage 3 : 17i3-hydroxy 11)8-24— (Π,ΙΓ-diaethylaminoethylthio) phenylj 17<-(orop-1 -r/nyl) estra 4-,9-dien-3-one.

Under inert gas 10.3 g of product obtained in Stage A are mixed with 72 cm5 of methanol, then 20.5 cm^ of 2Ii hydrochloric acid are added. The whole is kept under agitation at 20°C for 1 hour 15 minutes and neutralised by the addition' of‘‘a saturated aqueous solution of sodium bicarbonate, 200 co^of diethyl oxide are added, the whole is decanted and extracted with diethyl oxide, and ·*?*··· - · · 1C the combined--.organic phases are. washed with a saturated aquepus solution of sodium chloride, dried and concentrated to dryness. The' residue is chromatographed on silica, elution being carried out with the methylene chloride / methanol mixture (9:1) and 5 g °f expected product are obtained and crystallised by caking into a paste in diisopropyl oxide. Ii.Pt. = 145°G. = +125° - 2° (c = 1% chloroform).

The amine used at the start of Stage A was prepared as follows. g of sodium hydroxide in pellets are dissolved in 500 get’ of ethanol. In addition, 25-5 S °f chloroetbyl3 dicethylamine are dissolved in 75 ccr of ethanol, then 150 cm·5 of the sodium hydroxide solution prepared above are added. In addition, 30 g of parabromothiophenol are dissolved in 100 cm^ of ethanol, uhen 160 cm^ of the sodium hydroxide solution prepared above are added. Then, over 2 minutes,at 20°c, the amine solution prepared above is added. The whole is taken to reflux for 3 hours, the solvent is evaporated, water is added, the whole is extracted with Eethylene chloride, the organic phase is washed with a 0.1 II aqueous solution of sodium hydroxide then with wfeter and dried and the solvent is evaporated.

The residue is distilled and 35.5 6 of expected product are obtained. B.Pt. 0.1 » 110°C.

Example 29 : 11i3-(4-dinethylaminophenyl) 170-hydroxy 21-(trimethylsilyl) (17*) 19-nor pregna 4,9-dien-20-yn-5-one.

Stage A : 11 Under inert gas 13 cm5 of a 1.6 K solution of ethyl magnesium bromide in tetrahydrofuran are mixed with 15 cm-5 of anhydrous tetrahydrofuran. The mixture is agitated for 5 minutes at 0 to +5°C,then, drop by drop, 3.4 cm-’ of trimethylsilyl acetylene are added. The temperature is allowed to rise again to 20°C and the agitation is continued for 20 minutes then, drop by drop, a solution of 1.12 g of the product obtained in Stage A of Example 7 in 10 ctr5 of anhydrous tetrahydrofuran is introduced. The whole is kept for 16 hours at ambient temperature under agitation, poured into an aqueous solution of ammonium chloride, agitated for 10 minutes at ambient temperature and extracted with methylene chloride, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The 52585 residue is chromatographed on silica, elution being carried out with the petroleum ether / ethyl aceuate mixture (6:4) and 680 mg of expected product are obtained. = -75'.5° -3° (c = 0.5% chloroform).

Stage 3 : 11ft-(4-dimethylaminophenyl) 17^-hydroxy 21-(trimethylsilyl) (17 °<) 19-nor pregna 4,5-dlen-20-yr-5-one. 562 mg of the product obtained in Stage A are mixed with 15 cm^ of methanol and 1 cm^ of 2H hydrochloric acid. The mixture is kept under agitation at ambient temperature for 40 minutes, poured into an aqueous solution of sodium bicarbonate and extracted with ether, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the petroleum ether / ethyl acetate mixture (6:4) and 364 mg of expected product are obtained. = +97.5° - 3° (c = 0.35% chloroform).

Analysis : HC- Si (437.76) Calculated : C% 76.53 E% 8.47 2.87 Pound : 76.4 S.7 2.8 example 50 : 17^-hydroxy 11/?-C4-(r,-dimethylaminonethyl) phenyl! 1?*^-(prop-1-ynyl) estra 4,$-dien-5-one N-oxide. 1.4 g of product obtained in Example 25 are dissolved in 28 cm·’ of methylene chloride then, over 15 minutes at 0 to +5°C, a solution of 0.64 g of metachloroperbenzoic acid in 12.8 cm^ of methylene chloride is introduced. The whole is agitated for 1 hour at 0 to +5°C then poured into 595 a 0.2 77 acueous solution of sodium thiosulphate, decanted, extracted with methylene chloride, washed with an acueous solution of sodium bicarbonate, dried and evaporated to dryness. The residue is chromatographed on silica, elution being carried out with the methylene chloride / methanol mixture (8:2) and 1.28 g of expected product are obtained and dissolved in a methylene chloride / diisopropyl oxide mixture. The crystals formed are separated and dried and 1.075 S of expected product are obtained. M.Pfc. 215°C.

Mp = +74.5° - 2.5° (c = 0.7% chloroform).

Example 31 : Eemifumarate of 1?&-hydroxy 11($-Γ4-(ΐΓ,ΙΤdimethylaminomethyl) phenyl! 17<<"(?rop-1-ynyl) estra 4,9-dien-3-one. 1.44 g of the product obtained in Example 23 are mixed into 2.88 cm^ of ethanol then a mixture of 0.378 g of fumaric acid in 4.54 cm’ of ethanol is added. The suspension is agitated for 30 minutes at 60°C, the temperature is allowed to return to 20°C and the whole is kept under agitation. The solvent is evaporated, the residue is taken up with ether, separated and dried and 1.70 g of expected product are obtained. i-i.Et. = 160°C. ί i C«x3d = +70.5° ± 2=5° (o=0.8% chloroform).

Example 52 : 170-hydroxy 11/?-f4-(N,N-dipropylamino) phenyl! 17*-(prop-1-ynyl) estra 4,9-dien-3-one.

Stage A : 3.5-Γ1,2-ethane diyl bis (oxy)] 11^-^4-(9,If- ' -dipropylamino) phenyl] 17*-(prop-1-ynyl) estr-9-en 5^- j -171¾-diol. [ ( t i ii I.

I, I. r i! s' Preparation of the magnesium derivative.

Under inert gas 5 g o' magnesium are mixed with 15 ca^ of anhydrous tetrahydrofuren. Drop by drop, a solution of 52 g of 4-bromo Π,Ν-dipropylsniline in 11C cm^ of tetrahydrofuran is added, the temperature being kept at 40°G. A 1.1 K solution of expected magnesium derivative is thus obtained.

Condensation.

Under inert gas a solution of 5.55 6 of 3,5-Cl,210 -ethane diyl bis (oxy)3 5*-1C*-epoxy 17a:-(prop-1-ynyl) estr-9 (11)-en 17(5-01 obtained in Stage A of Example 7 is mixed with 200 mg of cuprous chloride. The mixture is agitated at 0 to +5°G then, over 15 minutes, 50 car’ of the solution of magnesium derivative obtained above are added, The whole is then agitated for Ί hour at 20°C, poured into a saturated aqueous solution of ammonium chloride and extracted with ether, the organic phase is dried and the solvent is evaporated. The residue is chromatographed on silica, elution being carried out with the toluene / ethyl acetate .mixture ¢7:3) and 6.3 g of expected product are obtained.

[D = -56° ± 2° (c = 0.6# chloroform).

Analysis : C^ H4q ITO^ (547-75) Calculated : C# 76.74 H# 9.02 IT# 2,56 Pound : 75.6 9.2 2.5 Stage 3 : 17ft-hydroxy 1lft-(4-(K,N-dipropylamino) phenyl) 17«<-(prop-1-ynyl) estra 4,9-dien-3-one. 52595 , To a solution of 5.83 g of product obtained in Stage A in SO cm^ of methanol are added 10 cm^ of 211 hydrochloric acid and the whole is agitated at 20°C for 50 minutes. It is neutralised by the addition of II sodium hydroxide, the solvent is evaporated under reduced pressure end the residue is taken up with methylene chloride. The organic phase is washed with water and dried and the solvent is evaporated. The residue is chromatographed on silica,, elution being carried out with the toluene / ethyl acetate mixture (75:25) and 3·81 g of expected product are obtained.

IS Spectrum (chloroform) Absorption at 3600 cm (OH), 1654 cm (C=0), 1610-1595-1558 and 1517 cm-1 (Δ4.9 + aromatic bands), 2'24C cm-1 (CsC).

The products below constitute examples of other products which can be obtained by the process of the invention : _ 11/3-r4-(U-ethyl IT-methylamino) phenyl! 17^-hydroxy 17*-(pr.op-1-ynyl) estra 4,9-dien-3-one (K.Pt. = 174°C; *D = +149° - 2.5°, C = 1% CKC13); - 17/S-hydroxy 11|i-fli-methyl 2,3-dihydro 1H-indol-5-yl! 17*-(prop-1-ynyl) estra 4,9-dien-3-ohe (K.Pt. = 176°C; = +133° i 3°, c = 0.8% CHClj); - 11(i-(4-dimethylaminophenyl) 3-hydroxyimino 17«-(prop-1-ynyl) estra 4,9-dien-17/?-ol, isomer S (K.Pt. = 260°C; = 141° ± 3-5°, c = 0.8% CHClj); - llB-(4-dimethylaminophenyl) 5-hydroxyimino 17«-(prop-1-yayl) estra 4,9-dien-17B-ol, isomer Ξ (M.Pt. =22O°C; Ojj - +164° i 5.5°, 0 - 0.8% CHClj); - 173-hydroxy llB-(a-pyrrolidylph.enyl) 17 aD - +88° ί 2.5° , 0— 0.75% CECl^); - 17E-hydroxy HE-Ca-N-methyl N-(l-methylethyl) aminophenyl] 170 , c - 0.5% CHClj); - 113-C4-(N,N-dimethylaminoethyloxy) phenyl] 173-hydroxy 17a-(prop-l-ynyl) estra a.,9-dien-3-one N-oxide, (a^ - +60.5° , c = 1.25« CHClj); - 17B-hydroxy llB-C(N-methyl) 2,3-dihydro lH-indol-5-yl] 17a-(prop-l-ynyl) estra 4,9-dien-3-one N-oxide, IS (aD - +103° i 2.5° , O «0.8% CHCl^); - 173-hydroxy 113-C4-(N-methyl N-trimethylsilylmethyl) aminophenyl) 17a-(prop-l-ynyl) estra 4,9-dien-3-one; - 173-hydroxy 113-Ca-(N-methyl N-dimethylaminoethyl) aminophenyl] 17a-(prop-l-ynyl) estra n,9-dien-3-one; - 17B-hydroxy 113-[h-(N-methyl piperazin-1-yl) phenyl] 17a-(prop-l-ynyl) estra 4,9-dien-3-one; - 17-hydroxyimino 11β-(4-dimethylaminophenyl) estra 4,9-dien-3-one, Ea3D « +207.5° 4 3.5°, (c « 1% OSC13); - 3(E)-hydroxyimino 17-hydroxyimino 113-(4-dimethylamino25 phenyl) estra 4,9-dien-3-one, (aD « +195° - 3° , = 15« CHClj); and - 5(Z)-hydroxyimino 17-hydroxyimino 113-(a-dimethylaminophenyl) estra 4,9~dien-3-one, (a^ « +163° - 2.5° , c «0.6% CHClj). i I j PHARMACOLOGICAL STUDY .Study of the activity of the products or. hormone receptors. _ : Kineralocortiooid receptor of the rat kidney. j ( Kale Sprague-Tawley EOPS rats, weighing 140 to 160 g, ' from which the suprarenal glands have been removed 4 to S J days previously, are sacrificed and their kidneys are perfused in situ with 50 »1 of a buffer of 10 mM of Tris, j I C.25 M saccharose and HC1 at pH 7.4. The kidneys are then ! removed, decapsulated and homogenised at O°C using a Potter polytetrafluoroethylene glass (7 g of tissue to 3 nil of buffer). The homogenate is centrifuged for 10 minutes at SCO g, at 0°C.

So as to eliminate the fixing of tritiated aldosterone I on .the glucocorticoid receptor, the Up, 17p-dihydroxy 21-methyl pregna 1,4,6-trien 20-yn 3-one steroid adhering ! solely to the glucocorticoid receptor is mixed with the i •*6 1 supernatant liquid at the final concentration of 10 M.

This supernatant liquid is ultracentrifuged at 105,000 g for 60 minutes at 0°C. Aliquot parts of the supernatant liquid -thus obtained are incubated at 0°C with a constant concentration (T) of tritiated aldosterone in the presence of increasing concentrations (0-25C0 . 10 7K) of cold aldosterone or of the cold product to be studied. After a period (t) of incubation, the concentration of bonded, tritiated aldosterone (3) is measured by the technique of adsorption to charcoal-dextran. 52585 Androgen receptor of the rat prostate gland.

Male Sprague-uawley SOPS rats of 150 to 200 g are castrated. 24 hours after castration, the animals are sacrificed; the prostate glands are removed, weighed and homogenised at 0°C using a Potter polytetrafluoroethylene glass in a TS.buffered solution (10 ml! of Tris, 0.25 H saccharose and ECI at pH 7·4) (1 g of tissue to 5 nil of TS). The homogenate is then ultracentrifuged (105,000 g x 60 minutes) at 0°C. Alicuot parts of the supernatant liquid thus obtained ere incubated at 0°C for two hours with a constant concentration (T) of product P (17j?-hydrcxy-17=i-methyl-estra-4,9,11-trien-5-one) in the presence of increasing concentrations (0 - 1,000 10-¾) either of cold ?,or of cold testosterone, or of the product to.be tested. The concentration of bonded tritiated P (3) is then measured in each incubate by the technique of adsorption to charcoal-dextran.

Progestogen receptor of the rabbit uterus.

Impubic feEale rabbits of about 1 kg receive a cutaneous application of 2> pg of estradiol. 5 days after this treatment, the animals are sacrificed; the uteri are removed, weighed and homogenised at 0°C using a Potter polytetrafluoroethylene glass in a TS buffered solution (10 mil of Tris, 0.25 K saccharose and HOI at 7.4) (1 g of tissue to 50 ml of TS).

The homogenate is then ultracentrifuged (105,000 g x 90 minutes) at 0°C. Aliquot parts of the supernatant liquid thus obtained are incubated at 0°C for a period (t) with a constant concentration (T) of tritiated product R (17,21-dimethyl 19-nor-4,S-pregnadiene-3,20-dione) in the presence of increasing concentrations (0 - 2,500 . 10 -'ll) either of cold E, or of cold progesterone, or of cold product to he tested. The concentration of bonded tritiated R (B) is then measured in each incubate by the technique of adsorption to charcoal-dextran.

Glucocorticoid receptor of the rat thymus.

Kale Sprague-3awley EOPS rats of 1S0 to 200 g have their suprarenal glands removed. 4 to 8 days after this removal, the animals are sacrificed and the thymi are removed and homogenised at 0°C in a buffer of 10 mK of Tris, 0.25 M saccharose, 2 mi-1 of dithiothreitol and ECI at pE 7Λ, using a Potter polytetrafluoroethylene glass (1 g of tissue to 10 ml of TS). The homogenate is then ultracentrifuged (105,000 g x SO minutes) at 0°C. Aliquot parts of the supernatant liquid thus obtained are incubated at 0°C for a period (t) with a constant concentration (T) of tritiated dexamethasone in the presence of increasing concentrations (0 - 2,500 . 10-¾) either of cold dexamethasone, or of the cold product to be tested. The concentration of the bonded tritiated dexamethasone (B) is then measured in each incubate by the technique of adsorption to charcoal-dextran.

Estrogen receptor of the mouse uterus.

Impubic female mice, 18 to 21 days oJi, are sacrificed; the uteri are removed, then homogenised at 0°C using a Potter polytetrafluoroethylene glass in a T3 buffered solution (10 mM of Tris, 0.25 M saccharose and HCl at pH 7.4) (1 g of tissue to 25 ml of TS). The homogenate is then ultracentrifuged (105,000 g x 9C minutes) at 0°C. Aliquot parts of the supernatant liquid thus obtained are incubated at 0°C for a period (t) with a constant concentration (T) of tritiated estradiol in the presence of increasing concentrations (0 - 1,000.10-¾) either of cold estradiol, or of the cold product to be tested. The concentration of bonded tritiated estradiol (B) is then measured in each incubate by the technique of adsorption to charcoal-dextran.

Calculation of the relative affinity of bonding.

The calculation of the relative affinity of bonding (RAB) is identical for all the receptors.

The following two curves are traced : the percentage of bonded tritiated hormone B as a function of the ! T ΐ i logarithm of the concentration of the cold reference hormone' and B as a function of the logarithm of the con- ί T ! centration of the cold product tested. : The straight line of the equation ! 50-k— max + — nin)/2 is determined. : T T B — max = percentage of the tritiated hormone bonded for T ; one incubation of this tritiated hormone at the concentr- j 100 82595 ation (Τ). •η = min = percentag® of the tritiated hormone bonded for T one incubation of this tritiated hormone at nhe concentration (T) in the presence of a large excess of cold hormone (2,500.10-¾).

The intersections of the straight line and of the curves enable the concentrations of the cold reference hormone (CK) and of nhe cold product tesred (CX),which inhibit by 50% the bonding of the tritiated hormone to the receptor, to be evaluated.

The relative affinity of bonding (RAB) of the product tested is determined by the equation = 100 (OX) The sesults obtained are as follows : 101 62585 1025258 5 Conclusion : The products studied and more particularly the products of examples 4, 17, 10, 16 and 22 show a very narked affinity for the glucocorticoid and progestogen receptors, as well as a slight affinity for the androgen receptor. On the other hand, these products do not show any activity with regard to the mineralocorticoid and estrogen receptors. :ro;a the results obtained, it may be concluded that 1C the products can show agonist or- antagonist activity towards glucocorticoids, progestogens and androgens.

II - Study of the anti-inflammatory activity of the product of Example 4.

The anti-inflammatory activity was investigated 1> according to the standard granuloma test.

In the technique used, a modification of the method of a. ;Tbl_:. and colleagues (Lxperientia, 1930, 6, 469), conventional female '..'istar rats, weighing from ICO to 110 g, receive an implant of two cotton-wool pellets, each-of 10 :..g, under the skin of the thorax. The sub-cutaneous treatment, which begins immediately after this im; lsnta-tion, lasts 2 „.eys at the rate of 2 injections per day; sixteen hour.-; after the last injection, that is on the third day,-ike animals are sacrificed. . c5 The pellets, surrounded with granuloma tissue formed, are weighed while fresh, then after standing for eighteen hours at 60°c .· the weight of the granuloma is obtained by 103 deducting the initial weight of the cotton-wool.

She thymi are also removed and weighed so as to determine the thymolytic activity of the product.

At the dose of 50 mg/kg administered by sub5 cutaneous route, the product of Example 4 does not show any anti-inflammatory glucocorticoid or thymolytic effect. Ill - Antiglucocorticoid activity.

She technique used comes from the method described by Daune and colleagues in i-iolecular Pharmacology 15, 94-8 - 955 (1977) She relationship between glucocorticoid structure and effects upon thymocytes, for mice thymocytes Thymocytes from rats, from which the suprarenal glands have been removed, are incubated at 57°C for 5 hours, in a O nutrient medium containing 5.10 H of dexamethasone, in the 15 presence or absence of a product to be studied at different concentrations. Tritiated uridine is added and the incubation is continued for one hour. The incubates are cooled, treated with a 5% solution of trichloroacetic acid, filtered on Whatman G3/A paper and washed three times with 2C a 5% solution of trichloroacetic acid. The radioactivity retained by the filter is determined.

The glucocorticoids and in particular dexamethasone cause a reduction in the incorporation of tritiated uridine, The products tested and, more particularly, products of Examples 4, 14, 8, 10, 11, 16, 6, 20 and 22 are contrary to this.effect. 104 ( ( ( ( ( Product of —s 5.10 Dexamethasone % inhibition of the ) ) example + Product tested effect of Dexamethasone; ) I" ( ( ( 4 10~8K 10"7M 30 70 ) ) ) ) ) ( ( 10~6M 90 (" ( ( ( ( ( 14 10~8M 10~7M 10"6M 18 57 * ) ) ) ) ) ) ( 10~8M 22 ) ) ( ( ( 8 10"7M 10"6M 53 * ) ) ) (- ( ( ( ( 10 10"SM 10~7M 1 o-6m 57 85 * ) ) ) ) ) ( ( ( ( ( 11 10~8M 10-7M 10"6M 14 54 75 ) ) ) ) (- ( 10"8M 28 ) ) ( ( ( '16 1 o"7m 10"6M SO 99 ) ) ) ( ( 6 10~SM 10_7M 10"6M 5 15 83 ) ) ) ! J 10-SM 4 Ί ) ) J ( ( 20 10~7M 10"6M 21 50 c ! 10"SM 16 22 10~7M 10"6M 69 * ) ) J.

At the dose of 10-¾, the inhibition of the effect of the dexamethasone was total. 105 It has, in addition, been established that, used alone, the products tested do not cause any effect of the the glucocorticoid type.

Conclusion : The products studied show a very marked anti-glucocorticoid activity, whilst being devoid of glucocorticoid activity.

Pharmaceutical compositions.

Compressed tablets were prepared, corresponding to the following formula : Product of Example 4 ............................. 50 mg Excipient (talc, search, magnesium stearate) q.s. for one compressed tablet up to .............120 mg. 106 82595

Claims (34)

1. Compounds with the fonnula (I 1 ) in which Rj represents an organic radical containing from 1 to 18

2. Compounds with the formula (I 1 ) as defined in claim 1,

3. Compounds with the formula (I 1 ) as defined in claim 1 or 2, in which Rg represents a methyl radical. 10

4. Compounds with the formula (I 1 ) as defined in claim 1, 2 or 3, in which X represents the residue of a ring with the formula: - ,: 2 - -! 'X 108 in which Rg retains the same significance as in claim 1, 2 or 3, the broken line at 16-17 symbolizes the possible presence of a double bond, Y represents a 5. Of an ester group, alk^ and alkg being defined as in claim 4 and R' 4 represents a hydrogen atom or an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, is prepared by submitting a compound with the formula (IV): to the action of a compound chosen from the group constituted by the compounds with the formula (R^gCuLi, R^-Hal and R^Li, in which R^ 119 and Hal are defined as in claim 18, if necessary, in the presence of a cuprous halide, so as to obtain the compound with the formula (V): which is submitted either to the action of a reducing agent, so as to obtain 5 the corresponding 17-hydroxy compound, or to the action of an appropriate magnesium compound, so as to obtain the corresponding substituted 170-hydroxy-17 - 120 52595 5 or a compound with the formula (I' A ), which, if the case arises, is converted by known methods into a derivative for which C=A represents a CH 2 group, and compounds with the formulae (I' A ), (I’ B ), (I' D ), (I' E ) or (I' F ), which, if the case arises, are submitted to the action of an acid so as to obtain a salt, or to the 5 which, if the case arises, is submitted either to the action of an etherifying agent able to introduce the alk; radical, so as to obtain a compound with the formula (1^): alkqQ d' E ) 116 or to the action of an esterifying agent able to introduce the CO alkg group in which alk^ retains its significance from claim 1, so as to obtain a compound with the formula (1^): 5 2 595 in which R represents a hydrogen atom or an alkg group, or to the action of a reducing agent able to reduce selectively the ketone function, so as to obtain the compound with the formula (I' D ): 5 or to the action of free hydroxylamine NHgOH or blocked in the form NHgO-alkg, in which alk 3 retains its significance as in claim 1, so as to obtain the compound with the formula (Ι'β): 115 5 -N-oxide of 21-chloro-9a,10a-epoxy-17e-hydroxy-llB-(4-dimethylaminophenyl)(17a)-19-nor-pregn-4-en-20-yn-3-one; -17e-hydroxy-lle-(4-dimethylaminophenyl)-17a-(prop-2-ynyl)estra4,9-dien-3-one; -N-oxide of 17e-hydroxy-11e-(4-dimethylaminophenyl)-17a-(prop-l-ynyl)

5. Compounds with the formula (I') as defined in claim 4, for which the ring D does not have an ethylene unsaturation, Rg and Rg each 5 radical in which alkg represents an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, or a -C=N radical, or Rg and R^ together form a radical CH, I HC-0 Z. I -C- ZI 2 5 radical in which n represents the numeral 1 or 2, R 5 represents a hydrogen atom, an alkyl radical containing from 1 to 8 carbon atoms, an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, an aryl radical containing from 6 to 14 carbon atoms, or an aralkyl radical containing from 7 to 15 carbon atoms, 5 answering to the formula (I): in which Rp Rg, X and A are defined as in claim 1. 5 carbon atoms, and containing at least a nitrogen, phosphorus or silicon atom, the atom immediately adjacent to the carbon at position 11 being a carbon atom, Rg represents a hydrocarbon radical containing from 1 to 8 carbon atoms, X represents the residue of a pentagonal or hexagonal ring, possibly

6. Compounds with the formula (I 1 ), as defined in any one of the claims 1 to 5, for which C=A represents an oxo group. 110

7. Compounds with the formula (I*) as defined in any one of the claims 1 to 6, for which Rj represents a hydrocarbon radical containing from 1 to 18 carbon atoms, and containing at least one nitrogen atom. 5

8. Compounds with the formula (Γ) as defined in claim 7, for which R^ represents a primary, secondary or tertiary alkyl radical, containing from 1 to 8 carbon atoms, including one or more heteroatoms chosen from the group constituted by oxygen, nitrogen and sulphur, of which at least one is a nitrogen atom or substituted by a

9. Compounds with the formula (I 1 ), as defined in claim 7, for which Rj represents a heterocycle radical including at least one nitrogen atom, possibly substituted by an alkyl radical containing from 1 to 8 carbon atoms.

10. Fora an epoxide bridge, and, a compound in which at the same time the radical R 1 includes an oxidized nitrogen atom and B and C together fora an epoxide bridge, which, if the case arises, is selectively reduced at the oxidized nitrogen atom contained in the radical Rp and which, if the case arises, is submitted to the action of an acid to obtain the salt. 117 10 action of an oxidizing agent, so as to obtain either, if the radical Rj includes a nitrogen atom, a derivative including at lie a radical of which the nitrogen atom is oxidized and in which the radicals B and C possibly form an epoxide bridge, or, if the radical R-] does not include a nitrogen atom, a derivative in which the radicals B and C 10 estra-4,9-dien-3-one. 10 heterocycle including at least one nitrogen atom. 10 in which represents a hydrogen atom, an alkyl radical or an acyl radical containing from 1 to 8 carbon atoms, and Zg an alkyl radical containing from 1 to 8 carbon atoms. 10 Rg identical to or different from R g , can take one of the values indicated for Rg and can equally represents a hydroxyl radical, each of R 3 and R^, being identical or different, represents either a hydrogen atom or an OH, Oalk^, O-CO-alkg, alk^ and alk g representing an alkyl radical containing from 1 to 8 carbon atoms or an aralkyl radical 10 substituted and possibly having an unsaturation, the group C=A at position 3 represents an oxo group, free or blocked in ketal form, a group OH Oal k. O-CO-alk, a C=NOH group,a C=N0-a1k 3 group, or a CHg group, alkp alkg, and 15 alk 3 representing an alkyl radical containing from 1 to 8 carbon atoms 107 or an aralkyl group containing from 7 to 15 carbon atoms and B and C together forming a double bond or an epoxide bridge, as well as their salts of addition with acids.

11. Compounds with the formula (I’) as defined in any one of the claims 1 to 10, for which Rj represents a 2-, 3-, or 4-pyridyl radical, - { ch 2 )-n x CHj radical, with (n >. 3)

12. Compounds with the formula (I'), as defined in any one of 10 the claims 1 to 11, in which Includes an oxidised nitrogen atom.

13. Any one of the compounds with the formula (!') the names of which follow: -1l6-[4-(N,N-dimethy1aminoethyloxy)phenyi]-178-hydroxy-17a(prop-1-ynyl)estra-4,9-dien-3-one; 112 -Π $-(4-dimethy1ami nophenyl)17g-hydroxy-17α-(prop-1-ynyl)estra-4,9dien-3-one; -N-oxide of 21-chi oro-17p-hydroxy-llg-(4-dimethyl ami nophenyl )(17a)19nor-pregna-4,9-dien-20-yn-3-one;

14. As medicaments, the compounds defined in any one of the claims 1 to 13 which are pharmaceutically acceptable, as well as their pharmaceutically acceptable salts of addition with acids. 15. At least one medicament defined in claim 14.

15. Pharmaceutical compositions containing as active principle 15 10. Compounds with the formula (I 1 ) as defined in claim 7, for which Rj represents an aryl or an aralkyl radical carrying an amine function -N in which Ry and Rg each represents an alkyl radical containing from1 to 8 carbon atoms or a primary, secondary or tertiary alkyl radical containing from 1 to 8 carbon atoms, carrying one or more heteroatoms chosen from the group constituted by oxygen, nitrogen and sulphur, of which at least one is a nitrogen atom, or substituted by a heterocycle including at least one nitrogen atom. Ill X 15 represent a hydrogen atom, and n is 1. 15 containing from 7 to 15 atoms, or an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, or a H -c-ch 2 oh, radical, or a -COCHgOCOalkg radical, in which alk g represents an alkyl radical containing from 1 to 8 carbon atoms, possibly substituted, 109 or an aralkyl radical containing from 7 to 15 carbon atoms, or a CO-COgH or CO-COg-alky radical, in which alky represents an alkyl radical containing from 1 to 8 carbon atoms, or a H NHalkg i I - C=0, radical, ora-C=0 ,

16. Preparation process for the compounds with the formula (I 1 ) as defined in any one of the claims 1 to 13, wherein a compound with the general formula (II): 113 53595 in which K represents a ketone group blocked in the ketal, thioketal, oxime or methyloxime form, Rp R 2 and X retain the same significance as in claim 1, is submitted 5 to the action of a dehydration agent, able to liberate the ketone function, so as to obtain a compound with the formula (I' A ) 114 which, if the case arises, is submitted either to the action of a ketalizing agent so as to obtain the compound with the formula (I’ B ) in. which the ketone function at position 3 is blocked in the ketal form,

17. Preparation process according to claim 16, wherein the starting compound used is a compound in which X is defined as in Claim 4.

18. Process according to claim 16 or 17, wherein the starting product with the formula (II) is prepared by submitting a compound with the formula (ill): (HI, to the action of a compound chosen from the group constituted by the compounds with the formula (R^gCuLi, Ft|MgHal and R-jLi, in which R^ retains the same significance as in claim 1 and Hal represents a halogen atom, if necessary in the presence of a cuprous halide, so as to obtain the corresponding compound with the formula (II).

19. Process according to claim 16 or 17, wherein the starting product, answering to formula (II 1 ), 118 62595 in which Rp Rg and K are defined as in claim 16, R'g represents a hydroxy radical or a radical 0R e , in which Rg represents the residue alk^ of an ether group or the residue COalkg

20. A process for the preparation of compounds of formula 1' as defined in claim 1 substantially as described herein with reference to Examples 1 to 31.

21. A compound of formula 1' as defined in claim 1 whenever prepared by 5 a process as claimed in any of claims 16 to 20.

22. Pharmaceutical compositions substantially as described herein by way of Example.

23. A compound of formula (II) as defined in claim 16.

24. A compound of formula (V) as defined in claim 19. 10

25. 116- [4-(trimethylsilyl) phenyl] 3, 3- [l,2-ethane diyl bis (oxyjj 17a -(prop-1-ynyl) estr-9-en 5a, 176 -diol.

26. Ils -(4-pyridyl) 3,3- [l,2-ethane diyl bis (oxy)] 17a-(prop-l-ynyl) estr-9-en 5a, 176-diol.

27. lie- [j-(N,N-dimethylamino) propyl] 3»3 [j,2-ethane diyl bis (oxyjj 15 17a-(prop-l-ynyl) estr-9-en 5a, 176-diol.

28. 116- (4-dimethyl ami nophenyl) 3,3- Jj ,2-ethane diyl bis (oxyjj 17a-(prop-l-ynyl) estr-9-en 5a, 176-diol.

29. 3,3- [ethane diyl bis (oxy)] 116- [4-(N,N-dimethyl-aminoethyloxy) phenyl] 17a-(prop-1-ynyl) estr-9-en 5a, 176-diol. 20

30. 21-chloro 3,3 [j ,2-ethane diyl bis (oxyjj 116-(4-dimethyl ami nophenyl) (17a) 19-nor pregn-9-en-20-yn 5a, 176-diol.

31. ll6-(4-dimethylaminophenyl) 3,3-[j ,2-ethane diyl bis (oxy)] 17a-(prop-2 ynyl) estr-9-en 5a, 176-diol.

32. 3,3 [l,2-ethane diyl bis (oxyjj5a 10a epoxy 17a-(1-propynl) estr-9(ll)25 en-17B-ol. - 121 52595

33. Process for preparing a compound claimed in any one of claims 23 to 32, which process is substantially as described herein.

34. A compound as claimed in any one of claims 23 to 32 whenever prepared by a process as claimed in claim 33.